N1-(3,3,3-trifluoro-2-hydroxo-2-methylpropionyl)-piperidine derivatives as inhibitors of pyruvate dehydrogenase kinase

ABSTRACT

Compounds of the formula (I) in which R, R 1  and R 3  have the meanings indicated in claim  1 , are inhibitors of pyruvate dehydrogenase kinase (PDHK), and can be employed, inter alia, for the treatment of diseases such as cancer.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to novel piperidine derivatives whichinhibit pyruvate dehydrogenase kinase (PDHK), to pharmaceuticalcompositions comprising them, to processes for their preparation, and totheir use in therapy for the treatment of cancers.

BACKGROUND OF THE INVENTION

Pyruvate dehydrogenase kinase (also pyruvate dehydrogenase complexkinase, PDC kinase, or PDHK) is a kinase enzyme which acts to inactivatethe enzyme pyruvate dehydrogenase by phosphorylating it using ATP.

PDHK thus participates in the regulation of the pyruvate dehydrogenasecomplex of which pyruvate dehydrogenase is the first component. BothPDHK and the pyruvate dehydrogenase complex are located in themitochondrial matrix of eukaryotes. The complex acts to convert pyruvate(a product of glycolysis in the cytosol) to acetyl-coA, which is thenoxidized in the mitochondria to produce energy, in the citric acidcycle. By downregulating the activity of this complex, PDHK willdecrease the oxidation of pyruvate in mitochondria and increase theconversion of pyruvate to lactate in the cytosol.

The opposite action of PDHK, namely the dephosphorylation and activationof pyruvate dehydrogenase, is catalyzed by a phosphoprotein phosphatasecalled pyruvate dehydrogenase phosphatase.

(Pyruvate dehydrogenase kinase should not be confused withPhosphoinositide-dependent kinase-1, which is also sometimes known as“PDK1”.)

There are four known isozymes of PDHK in humans: PDHK1-PDHK4.

Some studies have shown that cells that lack insulin (or are insensitiveto insulin) overexpress PDHK4. As a result, the pyruvate formed fromglycolysis cannot be oxidized which leads to hyperglycaemia due to thefact that glucose in the blood cannot be used efficiently. Thereforeseveral drugs target PDHK4 hoping to treat type II diabetes.

PDHK1 has shown to have increased activity in hypoxic cancer cells dueto the presence of HIF-1. PDHK1 shunts pyruvate away from the citricacid cycle and keeps the hypoxic cell alive. Therefore, PDHK1 inhibitionhas been suggested as an antitumor therapy since PDHK1 preventsapoptosis in these cancerous cells. Similarly, PDHK3 has been shown tobe overexpressed in colon cancer cell lines. Three proposed inhibitorsare AZD7545 and dichloroacetate which both bind to PDHK1, and Radicicolwhich binds to PDHK3.

Increasing PDC in the active form by inhibiting PDHK activity is a drugtarget for diabetes, heart disease and cancer.

EP 2 345 629 A1 discloses PDHK inhibitors which are considered to beuseful for the treatment or prophylaxis of diseases relating to glucoseutilization disorder, for example, diabetes (e.g., type 1 diabetes, type2 diabetes etc.), insulin resistance syndrome, metabolic syndrome,hyperglycemia and hyperlactacidemia. In addition, a PDHK inhibitor isconsidered to be useful for the treatment or prophylaxis of diabeticcomplications (e.g., neuropathy, retinopathy, nephropathy, cataractetc.). Furthermore, a PDHK inhibitor is considered to be useful for thetreatment or prophylaxis of diseases caused by limited energy substratesupply to the tissues, for example, cardiac failure, cardiomyopathy,myocardial ischemia, dyslipidemia and atherosclerosis. Additionally, aPDHK inhibitor is considered to be useful for the treatment orprophylaxis of cerebral ischemia or cerebral apoplexy. Moreover, a PDHKinhibitor is considered to be useful for the treatment or prophylaxis ofmitochondrial disease, mitochondrial encephalomyopathy, cancer and thelike.

Also, it is considered to be useful for the treatment or prophylaxis ofpulmonary hypertension.

LITERATURE

-   Wikipedia, pyruvate dehydrogenase kinase;-   T. E. Roche et al., Cell. Mol. Life Sci. 64 (2007) 830-849;-   A. Kumar et al., Chemico-Biological Interactions 199 (2012) 29-37;-   I. Papandreou et al., Int. J. Cancer: 128, 1001-1008 (2011);-   G. Sutendra et al., frontiers in oncology, 2013, vol. 3, 1-11.

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

It has been found that the compounds according to the invention andsalts thereof have very valuable pharmacological properties while beingwell tolerated.

The present invention specifically relates to compounds of the formula Iwhich inhibit PDHK, preferably PDHK2, to compositions which comprisethese compounds, and to processes for the use thereof for the treatmentof PDHK-induced diseases and complaints.

The compounds of the formula I can furthermore be used for the isolationand investigation of the activity or expression of PDHK. In addition,they are particularly suitable for use in diagnostic methods fordiseases in connection with unregulated or disturbed PDHK activity.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be determined by in vitro tests.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow active agents such as anti IgM to induce a cellularresponse such as expression of a surface marker, usually between aboutone hour and one week. In vitro testing can be carried out usingcultivated cells from blood or from a biopsy sample. The amount ofsurface marker expressed is assessed by flow cytometry using specificantibodies recognising the marker.

The dose varies depending on the specific compound used, the specificdisease, the patient status, etc. A therapeutic dose is typicallysufficient considerably to reduce the undesired cell population in thetarget tissue while the viability of the patient is maintained. Thetreatment is generally continued until a considerable reduction hasoccurred, for example an at least about, 50% reduction in the cellburden, and may be continued until essentially no more undesired cellsare detected in the body.

PRIOR ART

Fluorene derivatives are described as PDHK inhibitors for the treatmentof diseases such as diabetes and cancer in EP 2 345 629 A1.

Other pyrazole derivatives for use as TGR5 agonists are disclosed in WO2012/082947.

The preparation of pyrazolylaminopyrimidine derivatives for use as LRRK2modulators is described in WO 2012/062783.

The preparation of phenylmethyl-piperidinyl-triazolyl-pyridinyl-indazolederivatives for use as ERK inhibitors is described in WO 2012/058127.

The preparation of substituted pyrazoles and triazoles as novelprolylcarboxypeptidase inhibitors is described in WO 2011/143057.

Substituted piperidinylthiazole derivatives and analogs for thetreatment of diabetes and metabolic disorders are disclosed in WO2008/083238. Heteroarylpyrazoles as p38 kinase inhibitors are describedin U.S. Pat. No. 6,979,686 B1.

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula I

in which

-   R denotes pyrazol-diyl, imidazol-diyl, isoxazol-diyl or    triazol-diyl, each of which is unsubstituted or monosubstituted by    R²,-   R¹ denotes (CH₂)_(n)Ar, (CH₂)_(n)Het, A or Cyc,-   R² denotes A′, methoxy, hydroxymethyl, COOA′, CN, COOH, CONH₂ or OH,-   R³ denotes H, A′, COOA′ or CN,-   Ar denotes phenyl, which is unsubstituted or mono-, di-, tri-,    tetra- or pentasubstituted by Hal, A, CN, OA, [C(R⁵)₂]_(p)OH,    [C(R⁵)₂]_(p)N(R⁵)₂, NO₂, [C(R⁵)₂]_(p)COOR⁵, NR⁵COA, NR⁵SO₂A,    [C(R⁵)₂]_(p)SO₂N(R⁵)₂, S(O)_(n)A, O[C(R⁵)₂]_(m)N(R⁵)₂, NR⁵COOA,    NR⁵CON(R⁵)₂ and/or COA,-   Het denotes a mono- or bicyclic saturated, unsaturated or aromatic    heterocycle having 1 to 4 N, O and/or S atoms, which is    unsubstituted or mono- or disubstituted by Hal, A, CN, OA,    [C(R⁵)₂]_(p)OH, [C(R⁵)₂]_(p)N(R⁵)₂, NO₂, [C(R⁵)₂]_(p)COOR⁵, NR⁵COA,    NR⁵SO₂A, [C(R⁵)₂]_(p)SO₂N(R⁵)₂, S(O)_(n)A, O[C(R⁵)₂]_(m)N(R⁵)₂,    NR⁵COOA, NR⁵CON(R⁵)₂ and/or COA,-   Cyc denotes cyclic alkyl with 3, 4, 5, 6 or 7 C-atoms, which is    unsubstituted or monosubstituted by OH,-   A denotes unbranched or branched alkyl with 1-10 C-atoms, wherein    one or two non-adjacent CH- and/or CH₂-groups may be replaced by N-,    O- and/or S-atoms and/or wherein 1-7 H-atoms may be replaced by R⁴,-   R⁴ denotes F, Cl or OH,-   R⁵ denotes H oder A′,-   A′ denotes unbranched or branched alkyl with 1-6 C-atoms, wherein    1-5 H-atoms may be replaced by F,-   Hal denotes F, Cl, Br or I,-   m denotes 1, 2, 3 or 4,-   n denotes 0, 1 or 2,-   p denotes 0, 1, 2, 3 or 4    and pharmaceutically acceptable salts, tautomers and stereoisomers    thereof, including mixtures thereof in all ratios.

The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds.

Moreover, the invention relates to pharmaceutically acceptablederivatives of compounds of formula I.

The term solvates of the compounds is taken to mean adductions of inertsolvent molecules onto the compounds which form owing to their mutualattractive force. Solvates are, for example, mono- or dihydrates oralkoxides. It is understood, that the invention also relates to thesolvates of the salts. The term pharmaceutically acceptable derivativesis taken to mean, for example, the salts of the compounds according tothe invention and also so-called prodrug compounds.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound of formula I that can hydrolyze, oxidize, orotherwise react under biological conditions (in vitro or in vivo) toprovide an active compound, particularly a compound of formula I.Examples of prodrugs include, but are not limited to, derivatives andmetabolites of a compound of formula I that include biohydrolyzablemoieties such as biohydrolyzable amides, biohydrolyzable esters,biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzableureides, and biohydrolyzable phosphate analogues. In certainembodiments, prodrugs of compounds with carboxyl functional groups arethe lower alkyl esters of the carboxylic acid. The carboxylate estersare conveniently formed by esterifying any of the carboxylic acidmoieties present on the molecule. Prodrugs can typically be preparedusing well-known methods, such as those described by Burger's MedicinalChemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001,Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985,Harwood Academic Publishers Gmfh).

The expression “effective amount” denotes the amount of a medicament orof a pharmaceutical active ingredient which causes in a tissue, system,animal or human a biological or medical response which is sought ordesired, for example, by a researcher or physician.

In addition, the expression “therapeutically effective amount” denotesan amount which, compared with a corresponding subject who has notreceived this amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side-effects or also thereduction in the advance of a disease, complaint or disorder.

The expression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The invention also relates to the use of mixtures of the compounds ofthe formula I, for example mixtures of two diastereomers, for example inthe ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The concentrations of the isomeric formswill depend on the environment the compound is found in and may bedifferent depending upon, for example, whether the compound is a solidor is in an organic or aqueous solution.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI and pharmaceutically acceptable salts, solvates, tautomers andstereoisomers thereof, characterised in that a compound of the formulaII

-   -   in which R, R¹ and R³ have the meanings indicated in Claim 1,        is reacted with a compound of the formula III

-   -   in which L denotes Cl, Br, I or a free or reactively        functionally modified OH group,        and/or        a base or acid of the formula I is converted into one of its        salts.

Above and below, the radicals R, R¹ and R³ have the meanings indicatedfor the formula I, unless expressly stated otherwise.

A denotes alkyl, this is unbranched (linear) or branched, and has 1, 2,3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl,furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl ortert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2-or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl.

A preferably denotes unbranched or branched alkyl with 1-10 C-atoms,wherein one or two non-adjacent CH- and/or CH₂-groups may be replaced byN- and/or O-atoms and wherein 1-7 H-atoms may be replaced by R⁴.

A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 Catoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoroethyl.

Moreover, A denotes preferably CH₂OCH₃, CH₂CH₂OH or CH₂CH₂OCH₃. Cycdenotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl,preferably unsubstituted or monosubstituted by OH.

A′ denotes alkyl, this is unbranched (linear) or branched, and has 1, 2,3, 4, 5 or 6 C atoms. A′ preferably denotes methyl, furthermore ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermorealso pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-,2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl.

A′ very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6C atoms, wherein 1-3 H-atoms may be replaced by F.

R² preferably denotes A′, methoxy or hydroxymethyl, particularlypreferably H, methyl or trifluormethyl.

R³ preferably denotes H, methyl, ethyl, propyl, isopropyl, butyl,pentyl, hexyl or trifluormethyl, particularly preferably H, methyl ortrifluormethyl.

R⁵ preferably denotes H or methyl.

Ar denotes preferably o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m-or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- orp-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl,o-, m- or p-aminophenyl, o-, m- or p-(N-methylamino)phenyl, o-, m- orp-(N-methylaminocarbonyl)phenyl, o-, m- or p-methoxyphenyl, o-, m- orp-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- orp-(N,N-dimethylamino)phenyl, o-, m- orp-(N,N-dimethylaminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl,o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-(methylsulfonamido)phenyl, o-, m- or p-(methylsulfonyl)phenyl, o-, m-or p-cyanophenyl, o-, m- or p-carboxyphenyl, o-, m- orp-methoxycarbonylphenyl, o-, m- or p-acetylphenyl, o-, m- orp-aminosulfonylphenyl, o-, m- or p-[2-(morpholin-4-yl)ethoxy]phenyl, o-,m- or p-[3-(N,N-diethylamino)propoxy]phenyl, furthermore preferably2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-,2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-,2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or2-amino-6-chloro-phenyl, 2-nitro-4-N,N-dimethylamino- or3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-,2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methyl-phenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chloro-phenyl.

Ar furthermore preferably denotes phenyl, which is unsubstituted ormono-, di-, tri-, tetra- or pentasubstituted by Hal, A, CN and/or OA.

Irrespective of further substitutions, Het denotes, for example, 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, indazolyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-,6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-,4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-,4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-,7- or 8-2H-benzo-1,4-oxazinyl, further preferably 1,3-benzodioxol-5-yl,1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4-, -5-yl or2,1,3-benzoxadiazol-5-yl, azabicyclo[3.2.1]octyl or dibenzofuranyl.

The heterocyclic radicals may also be partially or fully hydrogenated.Irrespective of further substitutions, Het can thus also denote, forexample, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4-or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2-or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl,2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl,tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or-5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-,-3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or-6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl,tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or-5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or-5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-,-3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-,-4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermore preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl,3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl,2-oxo-2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzimidazolyl,1,3-dihydroindole, 2-oxo-1,3-dihydroindole or2-oxo-2,3-dihydrobenzimidazolyl.

Het preferably denotes denotes pyrimidyl, pyridyl, pyridazinyl,pyrazinyl, piperidinyl, pyrrolidinyl, pyrazolyl, thiazolyl, imidazolyl,furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl,oxadiazolyl or thiadiazolyl, each of which is unsubstituted or mono- ordisubstituted by Hal, A, CN and/or OA.

Hal preferably denotes F, Cl or Br, but also I, particularly preferablyF or Cl.

Throughout the invention, all radicals which occur more than once may beidentical or different, i.e. are independent of one another.

The compounds of the formula I may have one or more chiral centres andcan therefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to Ie, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   in Ia R² denotes A′, methoxy or hydroxymethyl;-   in Ib R³ denotes H or A′;-   in Ic Ar denotes phenyl, which is unsubstituted or mono-, di-, tri-,    tetra- or pentasubstituted by Hal, A, CN and/or OA;-   in Id Het denotes pyrimidyl, pyridyl, pyridazinyl, pyrazinyl,    piperidinyl, pyrrolidinyl, pyrazolyl, thiazolyl, imidazolyl,    furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl,    oxadiazolyl or thiadiazolyl, each of which is unsubstituted or mono-    or disubstituted by Hal, A, CN and/or OA;-   in Ie R denotes pyrazol-diyl, imidazol-diyl, isoxazol-diyl or    triazol-diyl, each of which is unsubstituted or monosubstituted by    R²    -   R¹ denotes (CH₂)_(n)Ar, (CH₂)_(n)Het, A or Cyc,    -   R² denotes A′, methoxy or hydroxymethyl,    -   R³ denotes H or A′,    -   Ar denotes phenyl, which is unsubstituted or mono-, di-, tri-,        tetra- or pentasubstituted by Hal, A, CN and/or OA,    -   Het denotes pyrimidyl, pyridyl, pyridazinyl, pyrazinyl,        piperidinyl, pyrrolidinyl, pyrazolyl, thiazolyl, imidazolyl,        furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl,        oxadiazolyl or thiadiazolyl, each of which is unsubstituted or        mono- or disubstituted by Hal, A, CN and/or OA,    -   Cyc denotes cyclic alkyl with 3, 4, 5, 6 or 7 C-atoms, which is        unsubstituted or monosubstituted by OH,    -   A denotes unbranched or branched alkyl with 1-10 C-atoms,        wherein one or two non-adjacent CH- and/or CH₂-groups may be        replaced by N-, O- and/or S-atoms and/or wherein 1-7 H-atoms may        be replaced by R⁴,    -   R⁴ denotes F, Cl or OH,    -   A′ denotes unbranched or branched alkyl with 1-6 C-atoms,        wherein 1-5 H-atoms may be replaced by F,    -   Hal denotes F, Cl, Br or I,    -   n denotes 0, 1 or 2,        and pharmaceutically acceptable salts, tautomers and        stereoisomers thereof, including mixtures thereof in all ratios.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], GeorgThieme-Verlag, Stuttgart), to be precise under reactionconditions which are known and suitable for the said reactions. Use canalso be made here of variants known per se which are not mentioned herein greater detail.

The starting compounds for the preparation of compounds of formula I aregenerally known. If they are novel, however, they can be prepared bymethods known per se.

Compounds of the formula I can preferably be obtained by reacting acompound of the formula II, with a compound of the formula III.

In the compounds of the formula III, L preferably denotes Cl, Br, I or afree or reactively modified OH group, such as, for example, an activatedester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferablymethylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxyhaving 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy).

The reaction is generally carried out in the presence of an acid-bindingagent, preferably an organic base, such as DIPEA, triethylamine,dimethylaniline, pyridine or quinoline.

The addition of an alkali or alkaline earth metal hydroxide, carbonateor bicarbonate or another salt of a weak acid of the alkali or alkalineearth metals, preferably of potassium, sodium, calcium or caesium, mayalso be favourable.

Preferably the reaction is carried out in the presence of[Dimethylamino([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluoro phosphate[HATU; coupling reagent] or in the presence of1-chloro-N,N,2-trimethyl-1-propenylamine.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° and140°, normally between −10° and 90°, in particular between about 0° andabout 70°.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Particular preference is given to acetonitrile, dichloromethane and/orDMF.

Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula Iare for the most part prepared by conventional methods. If the compoundof the formula I contains a carboxyl group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. The aluminium saltsof the compounds of the formula I are likewise included. In the case ofcertain compounds of the formula I, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoroacetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable acid-additionsalts of the compounds of the formula I include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,cyclopentane-propionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, formate,galacterate (from mucic acid), galacturonate, glucoheptanoate,gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate,heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate,lactate, lactobionate, malate, maleate, malonate, mandelate,metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(II), iron(III),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris(hydroxymethyl)methylamine(tromethamine), but this is not intended to represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

Particular preference is given to hydrochloride, dihydrochloride,hydrobromide, maleate, mesylate, phosphate, sulfate and succinate.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to: therespective free base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

Isotopes

There is furthermore intended that a compound of the formula I includesisotope-labelled forms thereof. An isotope-labelled form of a compoundof the formula I is identical to this compound apart from the fact thatone or more atoms of the compound have been replaced by an atom or atomshaving an atomic mass or mass number which differs from the atomic massor mass number of the atom which usually occurs naturally. Exam-ples ofisotopes which are readily commercially available and which can beincorporated into a compound of the formula I by well-known methodsinclude isotopes of hydrogen, carbon, nitrogen, oxygen, phos-phorus,fluo-rine and chlorine, for example ²H, ³H, ¹³O, ¹⁴O, ¹⁵N, ¹⁸O, ¹⁷O,³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. A compound of the formula I,a prodrug, thereof or a pharmaceutically acceptable salt of either whichcontains one or more of the above-mentioned isotopes and/or otheriso-topes of other atoms is intended to be part of the presentinvention. An isotope-labelled compound of the formula I can be used ina number of beneficial ways. For example, an isotope-labelled compoundof the formula I into which, for example, a radioisotope, such as ³H or¹⁴C, has been incorporated is suitable for medicament and/or substratetissue distribution assays. These radioisotopes, i.e. tritium (³H) andcarbon-14 (¹⁴C), are particularly preferred owing to simple preparationand excellent detectability. Incor-po-ra-tion of heavier isotopes, forexample deuterium (²H), into a compound of the formula I has therapeuticadvantages owing to the higher metabolic stability of thisisotope-labelled compound. Higher metabolic stability translatesdirectly into an increased in vivo half-life or lower dosages, whichunder most circumstances would represent a preferred embodi-ment of thepresent invention. An isotope-labelled compound of the formula I canusually be prepared by carrying out the procedures dis-closed in thesynthesis schemes and the related description, in the example part andin the preparation part in the present text, replacing anon-isotope-labelled reactant by a readily available isotope-labelledreactant.

Deuterium (²H) can also be incorporated into a compound of the formula Ifor the purpose in order to manipulate the oxidative metabolism of thecompound by way of the primary kinetic isotope effect. The primarykinetic isotope effect is a change of the rate for a chemical reactionthat results from exchange of isotopic nuclei, which in turn is causedby the change in ground state energies necessary for covalent bondformation after this isotopic exchange. Exchange of a heavier isotopeusually results in a lowering of the ground state energy for a chemicalbond and thus cause a reduction in the rate in rate-limiting bondbreakage. If the bond breakage occurs in or in the vicinity of asaddle-point region along the coordinate of a multi-product reaction,the product distribution ratios can be altered substantially. Forexplanation: if deuterium is bonded to a carbon atom at anon-exchangeable position, rate differences of k_(M)/k_(D)=2-7 aretypical. If this rate difference is successfully applied to a com-poundof the formula I that is susceptible to oxidation, the profile of thiscompound in vivo can be drastically modified and result in improvedpharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilledin the art attempts to optimise pharmacokinetic parameters whileretaining desirable in vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In vitro liver microsomal assays currentlyavailable provide valuable information on the course of oxidativemetabolism of this type, which in turn permits the rational design ofdeuterated compounds of the formula I with improved stability throughresistance to such oxidative metabolism. Significant improvements in thepharmacokinetic profiles of compounds of the formula I are therebyobtained, and can be expressed quantitatively in terms of increases inthe in vivo half-life (t1/2), concentration at maximum therapeuticeffect (C_(max)), area under the dose response curve (AUC), and F; andin terms of reduced clearance, dose and materials costs.

The following is intended to illustrate the above: a compound of theformula I which has multiple potential sites of attack for oxidativemetabolism, for example benzylic hydrogen atoms and hydrogen atomsbonded to a nitrogen atom, is prepared as a series of analogues in whichvarious combinations of hydrogen atoms are replaced by deuterium atoms,so that some, most or all of these hydrogen atoms have been replaced bydeuterium atoms. Half-life determinations enable favourable and accuratedetermination of the extent of the extent to which the improve-ment inresistance to oxidative metabolism has improved. In this way, it isdeter-mined that the half-life of the parent compound can be extended byup to 100% as the result of deuterium-hydrogen exchange of this type.

Deuterium-hydrogen exchange in a compound of the formula I can also beused to achieve a favourable modification of the metabolite spectrum ofthe starting compound in order to diminish or eliminate undesired toxicmetabolites. For example, if a toxic metabolite arises through oxidativecarbon-hydrogen (C—H) bond cleavage, it can reasonably be assumed thatthe deuterated analogue will greatly diminish or eliminate production ofthe unwanted metabolite, even if the particular oxidation is not arate-determining step. Further information on the state of the art withrespect to deuterium-hydrogen exchange may be found, for example inHanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J.Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985,Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al.Carcinogenesis 16(4), 683-688, 1993.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically acceptable salts,tautomers and stereoisomers thereof, including mixtures thereof in allratios, and optionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the condition treated,the method of administration and the age, weight and condition of thepatient, or pharmaceutical formulations can be administered in the formof dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbant, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tabletting machine, giving lumps of non-uniform shape, whichare broken up to form granules. The granules can be lubricated byaddition of stearic acid, a stearate salt, talc or mineral oil in orderto prevent sticking to the tablet casting moulds. The lubricated mixtureis then pressed to give tablets. The compounds according to theinvention can also be combined with a free-flowing inert excipient andthen pressed directly to give tablets without carrying out thegranulation or dry-pressing steps. A transparent or opaque protectivelayer consisting of a shellac sealing layer, a layer of sugar or polymermaterial and a gloss layer of wax may be present. Dyes can be added tothese coatings in order to be able to differentiate between differentdosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa prespecified amount of the compound. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds of the formula I and pharmaceutically acceptable salts,tautomers and stereoisomers thereof can also be administered in the formof liposome delivery systems, such as, for example, small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from various phospholipids, such as, forexample, cholesterol, stearylamine or phosphatidylcholines.

The compounds of the formula I and the pharmaceutically acceptablesalts, tautomers and physiologically functional derivatives thereof canalso be delivered using monoclonal antibodies as individual carriers towhich the compound molecules are coupled. The compounds can also becoupled to soluble polymers as targeted medicament carriers. Suchpolymers may encompass polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenolor polyethylene oxide polylysine, substituted by palmitoyl radicals. Thecompounds may furthermore be coupled to a class of biodegradablepolymers which are suitable for achieving controlled release of amedicament, for example polylactic acid, poly-epsilon-caprolactone,polyhydroxybutyric acid, polyorthoesters, polyacetals,polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions prepared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the formula Idepends on a number of factors, including, for example, the age andweight of the animal, the precise condition that requires treatment, andits severity, the nature of the formulation and the method ofadministration, and is ultimately determined by the treating doctor orvet. However, an effective amount of a compound according to theinvention is generally in the range from 0.1 to 100 mg/kg of body weightof the recipient (mammal) per day and particularly typically in therange from 1 to 10 mg/kg of body weight per day. Thus, the actual amountper day for an adult mammal weighing 70 kg is usually between 70 and 700mg, where this amount can be administered as a single dose per day orusually in a series of part-doses (such as, for example, two, three,four, five or six) per day, so that the total daily dose is the same. Aneffective amount of a salt or solvate or of a physiologically functionalderivative thereof can be determined as the fraction of the effectiveamount of the compound according to the invention per se. It can beassumed that similar doses are suitable for the treatment of otherconditions mentioned above.

A combined treatment of this type can be achieved with the aid ofsimultaneous, consecutive or separate dispensing of the individualcomponents of the treatment. Combination products of this type employthe compounds according to the invention.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically acceptable salts,tauotmers and stereoisomers thereof, including mixtures thereof in allratios, and at least one further medicament active ingredient.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound of the formula I and/or    pharmaceutically acceptable salts, tautomers and stereoisomers    thereof, including mixtures thereof in all ratios, and-   (b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound of theformula I and/or pharmaceutically acceptable salts, solvates andstereoisomers thereof, including mixtures thereof in all ratios,

and an effective amount of a further medicament active ingredient indissolved or lyophilised form.

“Treating” as used herein, means an alleviation, in whole or in part, ofsymptoms associated with a disorder or disease, or slowing, or haltingof further progression or worsening of those symptoms, or prevention orprophylaxis of the disease or disorder in a subject at risk fordeveloping the disease or disorder.

The term “effective amount” in connection with a compound of formula (I)can mean an amount capable of alleviating, in whole or in part, symptomsassociated with a disorder or disease, or slowing or halting furtherprogression or worsening of those symptoms, or preventing or providingprophylaxis for the disease or disorder in a subject having or at riskfor developing a disease disclosed herein, such as inflammatoryconditions, immunological conditions, cancer or metabolic conditions.

In one embodiment an effective amount of a compound of formula (I) is anamount that inhibits PDHK in a cell, such as, for example, in vitro orin vivo. In some embodiments, the effective amount of the compound offormula (I) inhibits PDHK in a cell by 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90% or 99%, compared to the activity of PDHK in an untreatedcell. The effective amount of the compound of formula (I), for examplein a pharmaceutical composition, may be at a level that will exercisethe desired effect; for example, about 0.005 mg/kg of a subject's bodyweight to about 10 mg/kg of a subject's body weight in unit dosage forboth oral and parenteral administration.

Use

The present invention specifically relates to compounds of the formula Iand pharmaceutically acceptable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios, for the use for thetreatment of cancer, diabetes and heart ischemia.

Moreover, the present invention relates to compounds of the formula Iand pharmaceutically acceptable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios, for the use for thetreatment of insulin resistance syndrome, metabolic syndrome,hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure,cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrialdisease, mitochondrial encephalomyopathy.

The present invention specifically relates to methods for treating orpreventing cancer, diabetes and heart ischemia, comprising administeringto a subject in need thereof an effective amount of a compound offormula I or a pharmaceutically acceptable salt, tautomer, stereoisomeror solvate thereof.

Also encompassed is the use of the compounds of the formula I and/orpharmaceutically acceptable salts, tautomers and stereoisomers thereoffor the preparation of a medicament for the treatment or prevention of aPDHK-induced disease or a PDHK-induced condition in a mammal, in whichto this method a therapeutically effective amount of a compoundaccording to the invention is administered to a sick mammal in need ofsuch treatment. The therapeutic amount varies according to the specificdisease and can be determined by the person skilled in the art withoutundue effort.

The expression “PDHK-induced diseases or conditions” refers topathological conditions that depend on the activity of PDHK. Diseasesassociated with PDHK activity include cancer, diabetes and heartischemia.

The present invention specifically relates to compounds of the formula Iand pharmaceutically acceptable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios, for the use for thetreatment of diseases in which the inhibition, regulation and/ormodulation inhibition of PDHK plays a role.

The present invention specifically relates to compounds of the formula Iand pharmaceutically acceptable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios, for the use for theinhibition of PDHK.

Representative cancers that compounds of formula I are useful fortreating or preventing include, but are not limited to, cancer of thehead, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx,chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder,uterine, cervix, breast, ovaries, testicles or other reproductiveorgans, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas,brain, central nervous system, solid tumors and blood-borne tumors.

Moreover, representative cancers that compounds of formula I are usefulfor treating or preventing include cancer of brain (gliomas),glioblastomas, leukemias, Bannayan-Zonana syndrome, Cowden disease,Lhermitte-Duclos disease, breast, inflammatory breast cancer, Wilm'stumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma,colon, head and neck, kidney, lung, liver, melanoma, ovarian,pancreatic, prostate, sarcoma, osteosarcoma, giant cell tumor of boneand thyroid.

Preferably, the present invention relates to a method wherein thedisease is a cancer.

Particularly preferable, the present invention relates to a methodwherein the disease is a cancer, wherein administration is simultaneous,sequential or in alternation with administration of at least one otheractive drug agent.

The disclosed compounds of the formula I can be administered incombination with other known therapeutic agents, including anticanceragents. As used here, the term “anticancer agent” relates to any agentwhich is administered to a patient with cancer for the purposes oftreating the cancer.

The anti-cancer treatment defined above may be applied as a monotherapyor may involve, in addition to the herein disclosed compounds of formulaI, conventional surgery or radiotherapy or medicinal therapy. Suchmedicinal therapy, e.g. a chemotherapy or a targeted therapy, mayinclude one or more, but preferably one, of the following anti-tumoragents:

Alkylating Agents

such as altretamine, bendamustine, busulfan, carmustine, chlorambucil,chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan,tosilate, lomustine, melphalan, mitobronitol, mitolactol, nimustine,ranimustine, temozolomide, thiotepa, treosulfan, mechloretamine,carboquone;apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman,trofosfamide, uramustine, TH-302⁴, VAL-083⁴;

Platinum Compounds

such as carboplatin, cisplatin, eptaplatin, miriplatine hydrate,oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin;lobaplatin, nedaplatin, picoplatin, satraplatin;

DNA Altering Agents

such as amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine,trabectedin, clofarabine;amsacrine, brostallicin, pixantrone, laromustine^(1,3);

Topoisomerase Inhibitors

such as etoposide, irinotecan, razoxane, sobuzoxane, teniposide,topotecan;amonafide, belotecan, elliptinium acetate, voreloxin;

Microtubule Modifiers

such as cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel,vinblastine, vincristine, vinorelbine, vindesine, vinflunine;fosbretabulin, tesetaxel;

Antimetabolites

such as asparaginase³, azacitidine, calcium levofolinate, capecitabine,cladribine, cytarabine, enocitabine, floxuridine, fludarabine,fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine,pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur;doxifluridine, elacytarabine, raltitrexed, sapacitabine, tegafur^(2,3),trimetrexate;

Anticancer Antibiotics

such as bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin,levamisole, miltefosine, mitomycin C, romidepsin, streptozocin,valrubicin, zinostatin, zorubicin, daunurobicin, plicamycin;aclarubicin, peplomycin, pirarubicin;

Hormones/Antagonists

such as abarelix, abiraterone, bicalutamide, buserelin, calusterone,chlorotrianisene, degarelix, dexamethasone, estradiol, fluocortolonefluoxymesterone, flutamide, fulvestrant, goserelin, histrelin,leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide,octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa,toremifene, trilostane, triptorelin, diethylstilbestrol;acolbifene, danazol, deslorelin, epitiostanol, orteronel,enzalutamide^(1,3);

Aromatase Inhibitors

such as aminoglutethimide, anastrozole, exemestane, fadrozole,letrozole, testolactone;formestane;

Small Molecule Kinase Inhibitors

such as crizotinib, dasatinib, erlotinib, imatinib, lapatinib,nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib,vandetanib, vemurafenib, bosutinib, gefitinib, axitinib;afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib,enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib,midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib,radotinib, rigosertib, tipifarnib, tivantinib, tivozanib, trametinib,pimasertib, brivanib alaninate, cediranib, apatinib⁴, cabozantinibS-malate^(1,3), ibrutinib^(1,3), icotinib⁴, buparlisib², cipatinib⁴,cobimetinib^(1,3), idelalisib^(1,3), fedratinib¹, XL-647⁴;

Photosensitizers

such as methoxsalen³;porfimer sodium, talaporfin, temoporfin;

Antibodies

such as alemtuzumab, besilesomab, brentuximab vedotin, cetuximab,denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab,trastuzumab, bevacizumab, pertuzumab^(2,3);catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab,necitumumab, nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab,ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab,zanolimumab, matuzumab, dalotuzumab^(1,2,3), onartuzumab^(1,3),racotumomab¹, tabalumab^(1,3), EMD-525797⁴, nivolumab^(1,3);

Cytokines

such as aldesleukin, interferon alfa², interferon alfa2a³, interferonalfa2b^(2,3);celmoleukin, tasonermin, teceleukin, oprelvekin^(1,3), recombinantinterferon beta-1a⁴;

Drug Conjugates

such as denileukin diftitox, ibritumomab tiuxetan, iobenguane I123,prednimustine, trastuzumab emtansine, estramustine, gemtuzumab,ozogamicin, aflibercept;cintredekin besudotox, edotreotide, inotuzumab ozogamicin, naptumomabestafenatox, oportuzumab monatox, technetium (99mTc) arcitumomab^(1,3),vintafolide^(1,3);

Vaccines

such as sipuleucel³; vitespen³, emepepimut-S³, oncoVAX⁴, rindopepimut³,troVax⁴, MGN-1601⁴, MGN-1703⁴;

Miscellaneous

alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid,imiquimod, lenalidomide, lentinan, metirosine, mifamurtide, pamidronicacid, pegaspargase, pentostatin, sipuleucel³, sizofiran, tamibarotene,temsirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid,vorinostat;celecoxib, cilengitide, entinostat, etanidazole, ganetespib, idronoxil,iniparib, ixazomib, lonidamine, nimorazole, panobinostat, peretinoin,plitidepsin, pomalidomide, procodazol, ridaforolimus, tasquinimod,telotristat, thymalfasin, tirapazamine, tosedostat, trabedersen,ubenimex, valspodar, gendicine⁴, picibanil⁴, reolysin⁴, retaspimycinhydrochloride^(,3), trebananib^(2,3), virulizin⁴, carfilzomib^(1,3),endostatin⁴, immucothel⁴, belinostat³, MGN-1703⁴; ¹ Prop. INN (ProposedInternational Nonproprietary Name)² Rec. INN (Recommended InternationalNonproprietary Names)³ USAN (United States Adopted Name)⁴ no INN.

The following abbreviations refer respectively to the definitions below:

aq (aqueous), h (hour), g (gram), L (liter), mg (milligram), MHz(Megahertz), min. (minute), mm (millimeter), mmol (millimole), mM(millimolar), m.p. (melting point), eq (equivalent), mL (milliliter), L(microliter), ACN (acetonitrile), AcOH (acetic acid), CDCl₃ (deuteratedchloroform), CD₃OD (deuterated methanol), CH₃CN (acetonitrile), c-hex(cyclohexane), DCC (dicyclohexyl carbodiimide), DCM (dichloromethane),DIC (diisopropyl carbodiimide), DIEA (diisopropylethyl-amine), DMF(dimethylformamide), DMSO (dimethylsulfoxide), DMSO-d₆ (deuterateddimethylsulfoxide), EDC(1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide), ESI (Electro-sprayionization), EtOAc (ethyl acetate), Et₂O (diethyl ether), EtOH(ethanol), HATU(dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammoniumhexafluorophosphate), HPLC (High Performance Liquid Chromatography),i-PrOH (2-propanol), K₂CO₃ (potassium carbonate), LC (LiquidChromatography), MeOH (methanol), MgSO₄ (magnesium sulfate), MS (massspectrometry), MTBE (Methyl tert-butyl ether), NaHCO₃ (sodiumbicarbonate), NaBH₄ (sodium borohydride), NMM (N-methyl morpholine), NMR(Nuclear Magnetic Resonance), PyBOP(benzotriazole-1-yl-oxy-trispyrrolidino-phosphoniumhexafluorophosphate), RT (room temperature), Rt (retention time), SPE(solid phase extraction), TBTU(2-(1-H-benzotriazole-1-yl)-1,1,3,3-tetramethyluromium tetrafluoroborate), TEA (triethylamine), TFA (trifluoroacetic acid), THF(tetrahydrofuran), TLC (Thin Layer Chromatography), UV (Ultraviolet).

Description of the In Vitro Assays Abbreviations:

-   GST=Glutathione-S-transferase-   FRET=Fluorescence resonance energy transfer-   HTRF®=(homogenous time resolved fluorescence)-   HEPES=4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid buffer-   DTT=Dithiothreitol-   BSA=bovine serum albumin-   CHAPS=3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate

Biochemical Activity Testing of PDHK2: PDC Inactivation Assay

The biochemical activity assay for PDHK2 is based on the inactivation ofPDC through phosphorylation by PDHK2. The assay is run in two steps: theenzymatic PDHK2 reaction in which isolated PDC is phosphorylated byPDHK2 with ATP as co-substrate and the PDC activity assay in whichpyruvate and NAD are converted to acetyl-CoA and NADH. The PDC activitycorrelates to the increase in NADH and thereby is detectable directlyvia the increasing fluorescence signal (Exc 340 nm, Em 450 nm).Inhibition of PDHK2 results in a lower phosphorylation status andthereby a less decrease in activity of PDC and a stronger increase inNADH fluorescence signal.

The PDC inactivation assay is performed in Greiner 384-well microtiterplates and is used for high throughput screen. 4 μl of PDHK2 (human,rec, Carna Bioscience, 10 ng/μl-137 nM final concentration) and PDC(isolated from porcine heart, Sigma-Aldrich, 20 mU/ml finalconcentration) are incubated in the absence or presence of the testcompound (10 dilution concentrations) for 30 min at room temperature inkinase buffer (15 mM potassium phosphate buffer, pH 7.0, 60 mM KCl, 1.5mM DTT, 2.5 mM MgCl₂, 0.0125% (w/v) BSA, 0.125% Pluronic F-68). Thekinase reaction is started by the addition of 4 μl ATP substratesolution (fc 5 μM in kinase buffer). After 30 min incubation at 37° C.40 μl of PDC reaction solution (100 mM Tris/HCl, pH 7.8, 0.5 mM EDTA, 1mM MgCl₂, 50 mM NaF, 0.25 mM Coenzyme A, 5 mM pyruvate, 1 mM NAD, 5 mMDTT, imM thiamine pyrophosphate) is added. The first fluorescencemeasurement is performed on a Perkin Elmer Envision (Exc 340 nm, Em 450nm). The reaction is incubated for 45 min at room temperature.Afterwards a second fluorescence measurement is performed and the PDCactivity is calculated by the difference between both measurements. Asfull value for the PDHK2 assay the inhibitor-free PDHK2 reaction isused. The pharmacological zero value used is DCA (Sigma-Aldrich) in afinal concentration of 3 mM. The inhibitory values (IC50) weredetermined using either the program Symyx Assay Explorer® or Condosseo®from GeneData.

Isothermal Titration Calorimetry

ITC measurements were performed with a VP-ITC micro calorimeter(Microcal, LLC/GE Healthcare Bio-Sciences AB, Uppsala, Sweden). Ingeneral titrations were performed by titrating the protein (50 μM) tothe test compound (5 μM) in 12 μl injections. All binding experimentswere carried out at 30° C. In general the test compounds were dilutedform DMSO stock solutions into the measurement buffer with a maximumfinal concentration of 1% DMSO. The measurement buffer was 20 mM HEPES,135 mM KCl, 1 mM TCEP, 2 mM MgCl₂, 15 mM NaH₂PO₄, pH 7.5. The humanPDHK2 (12-407) was produced in E. coli as his-tagged protein andpurified by affinity chromatography. The tag was removed by sidespecific proteolysis. Before titration the protein buffer was changed tothe measurement buffer containing the same DMSO concentration as thetest compound dilution. ITC data analysis was performed using Origin 7calorimetry software from the same supplier. For most measurements abinding model of one binding site was assumed. According to the appliedmathematical model it is possible to calculate the binding constant(K_(A)), the observed binding enthalpy (ΔH^(obs)) as well as thestoichiometry (N) of the formed complex. Preceding analysis the raw datawas corrected for the heats of dilution by extrapolating from thesaturation value from the end of titration. In order to allow for directcomparison between the respective experimental series and proteinpreparations the protein concentration was corrected by referencingtitrations to a well behaved standard inhibitor. The apparentstoichiometry values defined the fraction of binding competent proteinand compensated for relative errors in protein concentrationmeasurements. This corrected protein concentration was used to set upITC experiment series with test compounds. Any deviations from ideal 1:1stoichiometry observed here were attributed to errors in compoundconcentration. This nominal compound concentration was corrected as wellto achieve 1:1 stoichiometry in the fit.

Cellular Assay for Determination of Compound Activities

Compound activities were determined in a cellular immunofluorescenceassay. Human HEK293T cells were seeded into black 384-well plates withclear bottom and grown overnight.

Next day, test compounds were added to the wells and the platesincubated for 5 hours. Following this, cells were fixed withformaldehyde, permeabilised and blocked. The primary antibody,Anti-PDH-Elalpha (pSer300), AP1064 (Merck Millipore) was added andincubated overnight in the plate wells. Next, cells were washed and theseconday antibody, Alexa Fluor 488, goat anti-rabbit ab (A-11008,Invitrogen) was added together with Hoechst 33258 (H3569, Invitrogen)and incubated for 1 hour in the plate wells. Finally, cells were washedand the plates were measured on the laser scanning cytometer acumen hci(TTpLabtech).

The raw data were normalized against a pharmacological inhibitor controland dose response curves were generated by plotting the percent effectvalues using the software package Genedata screener (Genedata).

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means: water is added if necessary, thepH is adjusted, if necessary, to values between 2 and 10, depending onthe constitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate and evaporated, and the residue is purifiedby chromatography on silica gel and/or by crystallisation.

LC/MS:

HPLC-Method P:

Gradient: 3.3 min; Flow: 2.4 mI/min from 0 min 4% B, 2.8 min 100% B, 3.3min 100% B

A: Water+HCOOH (0.05% Vol.); B: Acetonitril+HCOOH (0.04% Vol.)

Column: Chromolith SpeedROD RP 18e 50-4.6

Wave Length: 220 nm

Agilent Apparatus

LC/MS:

HPLC-Method S:

Gradient: Flow: 2 ml/min from 0 min 5% B, 8.1 min 100% B, 8.5 min 5% B,10 min 5% B

A: Water+TFA (0.1% Vol.); B: Acetonitril+TFA (0.1% Vol.)

Column: XBridge C8, 3.5 m, 4.6×50 mm

Wave Length: 220 nm

¹H NMR was recorded on Bruker DPX-300, DRX-400, AVII-400 or BRUKER 500MHz spectrometer, using residual signal of deuterated solvent asinternal reference. Chemical shifts (6) are reported in ppm relative tothe residual solvent signal (δ=2.49 ppm for ¹H NMR in DMSO-d₆). ¹H NMRdata are reported as follows: chemical shift (multiplicity, couplingconstants, and number of hydrogens). Multiplicity is abbreviated asfollows: s (singlet), d (doublet), t (triplet), q (quartet), m(multiplet), br (broad).

EXAMPLES Pyrazolyl-Piperidine Derivatives

Example 1 Synthesis of(R)-3,3,3-trifluoro-2-hydroxy-2-methyl-1-[4-(2-p-tolyl-2H-pyrazol-3-yl)-piperidin-1-yl]-propan-1-one(“A1”) 1.1 4-((E)-3-Dimethylamino-acryloyl)-piperidine-1-carboxylic acidtert-butyl ester

4-Acetyl-piperidine-1-carboxylic acid tert-butyl ester (4.0 g, 17.6mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (50 mL) andheated to reflux (170° C. bath temperature). The mixture was stirredunder reflux for 64 h. The mixture was cooled down to ambienttemperature and evaporated under reduced pressure. This product was usedin the next step without further purification; yield: 4.7 g (84%) yellowcrystals; Rt: 1.85 min;

¹H NMR (400 MHz, CDCl₃): δ [ppm] 7.64-7.54 (d, J=12.5 Hz, 1H), 5.10-5.00(d, J=12.5 Hz, 1H), 4.21-4.02 (s, 2H), 3.12-2.69 (m, 8H), 2.43-2.34 (m,1H), 1.87-1.71 (m, 2H), 1.67-1.47 (m, 2H), 1.46-1.45 (s, 9H).

1.2 4-(2-p-Tolyl-2H-pyrazol-3-yl)-piperidine-1-carboxylic acidtert-butyl ester

4-((E)-3-Dimethylamino-acryloyl)-piperidine-1-carboxylic acid tert-butylester (0.5 g; 1.77 mmol) and p-tolylhydrazine hydrochloride (280.9 mg;1.77 mmol) were dissolved in absolute ethanol (40 mL) and heated toreflux. The mixture was stirred under reflux for 3 h and evaporatedunder reduced pressure. The residue was subjected toflash-chromatography (Isco CombiFlash® Rf, Column: Interchim PuriFlash®PF-50SIHP-JP/55G) using petrol ether/ethyl acetate, yield: 352 mg (46%),brown gum; Rt: 2.53 min.

1.3 4-(2-p-Tolyl-2H-pyrazol-3-yl)-piperidine hydrochloride

4-(2-p-Tolyl-2H-pyrazol-3-yl)-piperidine-1-carboxylic acid, tert-butylester (352.0 mg; 0.814 mmol) was dissolved in absolute ethanol (4 mL)and hydrochloric acid (25%; 2 mL) was added. The mixture was stirred for3 h at 25° C., 3 h at 50° C. and evaporated under reduced pressure. Themixture was subjected to RP-flash-chromatography (Isco Companion®,Column: Interchim puriFlash® IR-50C18/55G). Hydrochloric acid (25%) (2mL) was added to the pure fractions and lyophilized; yield: 127 mg(56%), off-white solid; Rt: 1.11 min; ¹H NMR (400 MHz, DMSO-d₆): δ [ppm]8.34 (s, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.33 (s, 3H), 6.27 (d, J=1.9 Hz,1H), 3.08 (dt, J=12.5, 3.1 Hz, 2H), 2.88 (tt, J=11.7, 3.7 Hz, 1H), 2.64(dd, J=12.6, 2.8 Hz, 2H), 2.39 (s, 3H), 1.80-1.72 (m, 2H), 1.67-1.52 (m,2H).

1.4(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(2-p-tolyl-2H-pyrazol-3-yl)-piperidin-1-yl]-propan-1-one(“A1”)

4-(2-p-Tolyl-2H-pyrazol-3-yl)-piperidine hydrochloride (122.0 mg; 0.439mmol) and (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (76.4mg; 0.483 mmol) were dissolved in DMF (1.0 mL) and the mixture wascooled in an ice bath.[Dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammoniumhexafluoro phosphate [HATU; coupling reagent] (200.4 mg; 0.527 mmol) andsubsequently N-ethyldiisopropylamine (0.187 mL; 1.1 mmol) were added,cooling was removed and the mixture was stirred for 20 h at 25° C. Themixture was directly purified using preparative HPLC (Agilent®, Column:Chromolith® prep 100-25). Pure fractions were lyophilized; yield: 81 mg(48%), white amorphous solid; (purity: 100%, Rt: 2.11 min, [M+H]+ 382);¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.54 (d, J=1.8 Hz, 1H), 7.34 (s, 4H),7.05 (s, 1H), 6.34-6.27 (m, 1H), 4.99-4.15 (m, 2H), 3.03-2.87 (m, 2H),2.64-2.47 (m, 1H), 2.39 (s, 3H), 1.87-1.68 (m, 2H), 1.64-1.36 (m, 5H).

The following compounds were prepared as described for Example 1 (“A1”):

(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-methyl-propan-1-one(“A2”)

4-[2-(4-Methoxy-phenyl)-2H-pyrazol-3-yl]-piperidine dihydrochloride(243.0 mg; 0.736 mmol) and(R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (127.9 mg; 0.809mmol) were dissolved in DMF (2 mL) and the mixture was cooled in an icebath. HATU (335.7 mg; 0.883 mmol) and subsequentlyN-ethyldiisopropylamine (0.5 mL; 2.943 mmol) were added, cooling wasremoved and the mixture was stirred for 4 h at 25° C. The mixture wassubjected to RP-flash-chromatography (Isco Companion®); Column:Interchim puriFlash® IR-50C18/205G) and the pure fractions werelyophilized; yield: 230 mg (79%), light yellow solid; (purity: 100%, Rt:2.01 min, [M+H]⁺ 398); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.54 (d, J=1.8Hz, 1H), 7.42-7.34 (m, 2H), 7.16-6.91 (m, 3H), 6.30 (s, 1H), 4.72 (s,1H), 4.41 (s, 1H), 3.84 (s, 3H), 3.05-2.83 (m, 2H), 2.67-2.52 (m, 1H),1.87-1.71 (m, 2H), 1.65-1.37 (m, 5H).

2-{5-[1-((R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-pyrazol-1-yl}-benzonitrile(“A3”)

2-(5-Piperidin-4-yl-pyrazol-1-yl)-benzonitrile hydrochloride (102.2 mg;0.354 mmol) and (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid(67.2 mg; 0.425 mmol) were dissolved in DMF (1 mL) and the mixture wascooled in an ice bath. HATU (201.9 mg; 0,531 mmol) and subsequentlyN-ethyldiisopropylamine (0.15 mL; 0.885 mmol) were added, cooling wasremoved and the mixture was stirred for 20 h at 25° C. The mixture wasdirectly purified using preparative HPLC (Agilent®, Column: Chromolith®prep 100-25). Pure fractions were lyophilized; yield: 7 mg (5%),amorphous colorless solid; (purity: 100%, Rt: 2.03 min, [M+H]⁺ 393); ¹HNMR (400 MHz, DMSO-d₆) δ [ppm] 8.73 (d, J=4.5 Hz, 1H), 8.30-8.22 (m,1H), 7.87 (d, J=8.7 Hz, 1H), 7.70-7.62 (m, 1H), 7.45 (d, J=4.6 Hz, 1H),7.35-7.27 (m, 1H), 7.10 (s, 1H), 1.95-1.64 (m, 2H), 5.12-4.49 (m, 2H),4.15-4.00 (m, 1H), 3.41-3.21 (m, 1H), 3.08-2.83 (m, 1H), 2.37-2.19 (m,2H), 1.58 (s, 3H).

(R)-3,3,3-Trifluoro-1-{4-[2-(2-fluoro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A4”)

4-[2-(2-Fluoro-phenyl)-2H-pyrazol-3-yl]-piperidine hydrochloride (99.7mg; 0.354 mmol) and (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionicacid (67.2 mg; 0.425 mmol) were dissolved in DMF (1 mL) and the mixturewas cooled in an ice bath. HATU (201.9 mg; 0,531 mmol) and subsequentlyN-ethyldiisopropylamine (0.15 mL; 0.885 mmol) were added, cooling wasremoved and the mixture was stirred for 20 h at 25° C. The mixture wasdirectly purified using preparative HPLC (Agilent®, Column: Chromolith®prep 100-25). Pure fractions were lyophilized; yield: 10 mg (7%) beigeamorphous solid; (purity: 100%, Rt: 1.99 min, [M+H]⁺ 386); ¹H NMR (400MHz, DMSO-d₆) δ [ppm] 7.66-7.57 (m, 2H), 7.57-7.51 (m, 1H), 7.51-7.44(m, 1H), 7.43-7.35 (m, 1H), 7.00 (s, 1H), 6.34 (s, 1H), 4.89-4.21 (m,2H), 3.09-2.78 (m, 1H), 2.76-2.64 (m, 1H), 2.61-2.40 (m, 1H), 1.83-1.64(m, 2H), 1.64-1.34 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(2-o-tolyl-2H-pyrazol-3-yl)-piperidin-1-yl]-propan-1-one(“A5”)

4-(2-o-Tolyl-2H-pyrazol-3-yl)-piperidine hydrochloride (98.3 mg; 0.354mmol) and (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (67.2mg; 0.425 mmol) were dissolved in DMF (1 mL) and the mixture was cooledin an ice bath. HATU (201.9 mg; 0,531 mmol) and subsequentlyN-ethyldiisopropylamine (0.15 mL; 0.885 mmol) were added, cooling wasremoved and the mixture was stirred for 20 h at 25° C. The mixture wasdirectly purified using preparative HPLC (Agilent®, Column: Chromolith®prep 100-25). Pure fractions were lyophilized; yield: 18 mg (13%) beigeamorphous solid; (purity: 100%, Rt: 2.07 min, [M+H]+ 382); ¹H NMR (400MHz, DMSO-d₆) δ [ppm] 7.57 (d, J=1.8 Hz, 1H), 7.48-7.39 (m, 2H),7.39-7.32 (m, 1H), 7.32-7.27 (m, 1H), 6.99 (s, 1H), 6.30 (d, J=1.9 Hz,1H), 4.79-4.24 (m, 2H), 2.98-2.75 (m, 1H), 2.64-2.40 (m, 2H), 1.92 (s,3H), 1.79-1.62 (m, 2H), 1.58-1.36 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(2-m-tolyl-2H-pyrazol-3-yl)-piperidin-1-yl]-propan-1-one(“A6”)

4-(2-m-Tolyl-2H-pyrazol-3-yl)-piperidine hydrochloride (98.3 mg; 0.354mmol) and (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (67.2mg; 0.425 mmol) were dissolved in DMF (1 mL) and the mixture was cooledin an ice bath. HATU (201.9 mg; 0,531 mmol) and subsequentlyN-ethyldiisopropylamine (0.15 mL; 0.885 mmol) were added, cooling wasremoved and the mixture was stirred for 20 h at 25° C. The mixture wasdirectly purified using preparative HPLC (Agilent®, Column: Chromolith®prep 100-25). Pure fractions were lyophilized; yield: 17 mg (13%) beigeamorphous solid; (purity: 100%, Rt: 2.12 min, [M+H]⁺ 382);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 7.55 (d, J=1.8 Hz, 1H), 7.42 (t, J=7.7Hz, 1H), 7.32-7.22 (m, 3H), 7.01 (s, 1H), 6.31 (s, 1H), 4.84-4.28 (m,2H), 3.06-2.81 (m, 2H), 2.67-2.46 (m, 1H), 2.39 (s, 3H), 1.87-1.71 (m,2H), 1.68-1.39 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[2-(2-methoxy-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-methyl-propan-1-one(“A7”)

4-[2-(2-Methoxy-phenyl)-2H-pyrazol-3-yl]-piperidine hydrochloride (104.0mg; 0.354 mmol) and (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionicacid (67.2 mg; 0.425 mmol) were dissolved in DMF (1 mL) and the mixturewas cooled in an ice bath. HATU (201.9 mg; 0,531 mmol) and subsequentlyN-ethyldiisopropylamine (0.15 mL; 0.885 mmol) were added, cooling wasremoved and the mixture was stirred for 20 h at 25° C. The mixture wasdirectly purified using preparative HPLC (Agilent®, Column: Chromolith®prep 100-25). Pure fractions were lyophilized; yield: 6 mg (4%) beigeamorphous solid; (purity: 100%, Rt: 1.96 min, [M+H]+ 398).

3-{5-[1-((R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-pyrazol-1-yl}-benzonitrile(“A8”)

3-(5-Piperidin-4-yl-pyrazol-1-yl)-benzonitrile hydrochloride (102.2 mg;0.354 mmol) and (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid(67.2 mg; 0.425 mmol) were dissolved in DMF (1 mL) and the mixture wascooled in an ice bath. HATU (201.9 mg; 0,531 mmol) and subsequentlyN-ethyldiisopropylamine (0.15 mL; 0.885 mmol) were added, cooling wasremoved and the mixture was stirred for 20 h at 25° C. The mixture wasdirectly purified using prep. HPLC (Agilent®, Column: Chromolith® prep100-25). Pure fractions were lyophilized; yield: 9 mg (6%) beigeamorphous solid; (purity: 100%, Rt: 1.99 min, [M+H]⁺ 393).

4-{5-[1-((R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-pyrazol-1-yl}-benzonitrile(“A9”)

4-(5-Piperidin-4-yl-pyrazol-1-yl)-benzonitrile hydrochloride (102.2 mg;0.354 mmol) and (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid(67.2 mg; 0.425 mmol) were dissolved in DMF (1 mL) and the mixture wascooled in an ice bath. HATU (201.9 mg; 0,531 mmol) and subsequentlyN-ethyldiisopropylamine (0.15 mL; 0.885 mmol) were added, cooling wasremoved and the mixture was stirred for 20 h at 25° C. The mixture wasdirectly purified using preparative HPLC (Agilent®, Column: Chromolith®prep 100-25). Pure fractions were lyophilized; yield: 6 mg (4%) beigeamorphous solid; (purity: 100%, Rt: 2.01 min, [M+H]⁺ 393).

(R)-3,3,3-Trifluoro-1-{4-[2-(3-fluoro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A10”)

4-[2-(3-Fluoro-phenyl)-2H-pyrazol-3-yl]-piperidine hydrochloride (99.7mg; 0.354 mmol) and (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionicacid (67.2 mg; 0.425 mmol) were dissolved in DMF (1 mL) and the mixturewas cooled in an ice bath. HATU (201.9 mg; 0,531 mmol) and subsequentlyN-ethyidiisopropylamine (0.15 mL; 0.885 mmol) were added, cooling wasremoved and the mixture was stirred for 20 h at 25° C. The mixture wasdirectly purified using preparative HPLC (Agilent®, Column: Chromolith®prep 100-25). Pure fractions were lyophilized; yield: 14 mg (10%) beigeamorphous solid; (purity: 100%, Rt: 2.08 min, [M+H]⁺ 386); ¹H NMR (400MHz, DMSO-d₆) δ [ppm] 7.64-7.54 (m, 2H), 7.43-7.30 (m, 3H), 7.01 (s,1H), 6.35 (s, 1H), 4.86-4.28 (m, 2H), 3.16-2.37 (m, 3H), 1.89-1.72 (m,2H), 1.64-1.38 (m, 5H).

(R)-1-{4-[2-(2-Chloro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A11”)

4-[2-(2-Chloro-phenyl)-2H-pyrazol-3-yl]-piperidine hydrochloride (105.6mg; 0.354 mmol) and (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionicacid (67.2 mg; 0.425 mmol) were dissolved in DMF (1 mL) and the mixturewas cooled in an ice bath. HATU (201.9 mg; 0,531 mmol) and subsequentlyN-ethyldiisopropylamine (0.15 mL; 0.885 mmol) were added, cooling wasremoved and the mixture was stirred for 20 h at 25° C. The mixture wasdirectly purified using preparative HPLC (Agilent®, Column: Chromolith®prep 100-25). Pure fractions were lyophilized; yield: 48 mg (34%) beigeamorphous solid; (purity: 100%, Rt: 2.06 min, [M+H]⁺ 402-404); ¹H NMR(400 MHz, DMSO-d₆) δ [ppm]7.74-7.68 (m, 1H), 7.63-7.53 (m, 4H), 7.00 (s,1H), 6.36-6.29 (m, 1H), 4.78-4.26 (m, 2H), 3.02-2.76 (m, 1H), 2.62-2.39(m, 2H), 1.78-1.66 (m, 2H), 1.62-1.38 (m, 5H).

(R)-1-{4-[2-(3-Chloro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A12”)

4-[2-(3-Chloro-phenyl)-2H-pyrazol-3-yl]-piperidine hydrochloride (105.6mg; 0.354 mmol) and (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionicacid (67.2 mg; 0.425 mmol) were dissolved in DMF (1 mL) and the mixturewas cooled in an ice bath. HATU (201.9 mg; 0,531 mmol) and subsequentlyN-ethyldiisopropylamine (0.15 mL; 0.885 mmol) were added, cooling wasremoved and the mixture was stirred for 20 h at 25° C. The mixture wasdirectly purified using preparartive HPLC (Agilent®, Column: Chromolith®prep 100-25). Pure fractions were lyophilized; yield: 32 mg (22%)off-white oil; (purity: 100%, Rt: 2.18 min, [M+H]⁺ 402-404); ¹H NMR (400MHz, DMSO-d₆) δ [ppm] 7.62-7.53 (m, 4H), 7.50-7.44 (m, 1H), 7.10-6.89(m, 1H), 6.37-6.33 (m, 1H), 4.83-4.28 (m, 2H), 3.08-2.94 (m, 2H),2.73-2.51 (m, 1H), 1.87-1.73 (m, 2H), 1.62-1.38 (m, 5H).

(R)-1-{4-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A13”)

4-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-piperidine (92.0 mg; 0.351 mmol)and1-[1-((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-cyclopropanecarboxylicacid ethyl ester (66.7 mg; 0.422 mmol) were dissolved DMF (1 mL) and themixture was cooled in an ice bath. HATU (200.5 mg; 0.527 mmol) andsubsequently N-ethyldiisopropylamine (0.15 mL; 0.879 mmol) were added,cooling was removed and the mixture was stirred for 20 h at 25° C. Themixture was directly purified using preparative HPLC (Agilent®, Column:Chromolith® prep 100-25). Pure fractions were lyophilized; yield: 55 mg(39%) light beige solid; (purity: 100%, Rt: 2.13 min, [M+H]+ 402-404);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.62-7.57 (m, 3H), 7.54-7.49 (m, 2H),7.01 (s, 1H), 6.37-6.32 (m, 1H), 4.84-4.23 (m, 2H), 3.06-2.90 (m, 2H),2.70-2.51 (m, 1H), 1.86-1.72 (m, 2H), 1.59-1.40 (m, 5H).

(R)-3, 3,3-Trifluoro-1-{4-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A14”)

4-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-piperidine (94.0 mg; 0.383 mmol)and1-[1-((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-cyclopropanecarboxylicacid ethyl ester (72.7 mg; 0.460 mmol) were dissolved in DMF (1 mL) andthe mixture was cooled in an ice bath. HATU (218.6 mg; 0.575 mmol) andsubsequently N-ethyldiisopropylamine (0.16 mL; 0.958 mmol) were added,cooling was removed and the mixture was stirred for 20 h at 25° C. Themixture was directly purified using preparative HPLC (Agilent®, Column:Chromolith® prep 100-25). Pure fractions were lyophilized; yield: 74 mg(50%); (purity: 100%, Rt: 2.03 min, [M+H]⁺ 386);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.56 (d, J=1.8 Hz, 1H), 7.55-7.48 (m,2H), 7.42-7.33 (m, 2H), 7.01 (s, 1H), 6.36-6.29 (m, 1H), 4.91-4.24 (m,2H), 3.06-2.86 (m, 2H), 2.73-2.52 (m, 1H), 1.87-1.71 (m, 2H), 1.64-1.34(m, 5H).

(R)-1-{4-[2-(3-Chloro-2-fluoro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A15”)

4-[2-(3-Chloro-2-fluoro-phenyl)-2H-pyrazol-3-yl]-piperidine (85.0 mg;0.304 mmol) and (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid(57.6 mg; 0.365 mmol) were dissolved in DMF (2 mL) and the mixture wascooled in an ice bath. HATU (173.3 mg; 0.456 mmol) and subsequentlyN-ethyldiisopropylamine (0.13 mL; 0.760 mmol) were added, cooling wasremoved and the mixture was stirred for 20 h at 25° C. The mixture wasdirectly purified using preparative HPLC (Agilent®, Column: Chromolith®prep 100-25). Pure fractions were lyophilized; yield: 75 mg (59%)off-white solid; (purity: 100%, Rt: 2.07 min, [M+H]⁺ 420-422); ¹H NMR(500 MHz, DMSO-d₆) δ [ppm] 7.83-7.78 (m, 1H), 7.65 (d, J=1.8, 1H),7.59-7.53 (m, 1H), 7.42 (td, J=8.1, 1.3 Hz, 1H), 7.01 (s, 1H), 6.38 (s,1H), 4.89-4.20 (m, 2H), 3.09-2.83 (m, 1H), 2.79-2.67 (m, 1H), 2.66-2.41(m, 1H), 1.79-1.69 (m, 2H), 1.63-1.40 (m, 5H).

(R)-3,3,3-Trifluoro-1-{4-[2-(2-fluoro-4-methyl-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A16”)

4-[2-(2-Fluoro-4-methyl-phenyl)-2H-pyrazol-3-yl]-piperidine (80.0 mg;0.308 mmol) and (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid(58.5 mg; 0.370 mmol) were dissolved in DMF (2 mL) and the mixture wascooled in an ice bath. HATU (176 mg; 0.463 mmol) and subsequentlyN-ethyldiisopropylamine (0.13 mL; 0.771 mmol) were added, cooling wasremoved and the mixture was stirred for 20 h at 25° C. The mixture wasdirectly purified using prep. HPLC (Agilent®, Column: Chromolith® prep100-25). Pure fractions were lyophilized; yield: 48 mg (39%) off-whitesolid; (purity: 100%, Rt: 2.09 min, [M+H]⁺ 400); ¹H NMR (500 MHz,DMSO-d₆) δ [ppm] 7.59 (d, J=1.8 Hz, 1H), 7.39 (t, J=8.1 Hz, 1H),7.32-7.28 (m, 1H), 7.21-7.16 (m, 1H), 7.00 (s, 1H), 6.31 (s, 1H),4.91-4.19 (m, 2H), 3.09-2.75 (m, 1H), 2.73-2.61 (m, 1H), 2.61-2.48 (m,1H), 2.42 (s, 3H), 1.78-1.65 (m, 2H), 1.64-1.34 (m, 5H).

(R)-1-[4-(2-tert-Butyl-2H-pyrazol-3-yl)-piperidin-1-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A17”)

4-(2-tert-Butyl-2H-pyrazol-3-yl)-piperidine dihydrochloride (107.0 mg;0.359 mmol) and (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-propionic acid(115.7 mg; 0.717 mmol) were dissolved in DMF (3 mL). The yellow solutionwas cooled down with a water-ice-bath while stirring.N-Ethyldiisopropylamine (0.90 mL; 5.292 mmol) and HATU (299.9 mg; 0.789mmol) was added. The ice-bath was removed and the yellow solution wasstirred at room temperature for 14 h. The solution was cooled down withan ice-bath. (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-propionic acid (57.8mg; 0.359 mmol), N-ethyldiisopropylamine (0.06 ml; 0.359 mmol) and HATU(204.5 mg; 0.538 mmol) were added. After 15 minutes the ice bath wasremoved. The solution was stirred at room temperature for another 90minutes. The reaction mixture was diluted with water and extracted withethyl acetate. The organic layers were combined, washed with water andbrine, dried with sodium sulfate, filtrated by suction and evaporated todryness. The residue was purified by preparative HPLC (Agilent®, Column:SunFire™ Prep C18 OBD™ 5 μM; 30×150 mm). Pure fractions werelyophilized; yield: 81 mg (65%), colorless solid; (purity 100%, Rt: 1.93min, [M+H]⁺ 348);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.22 (d, J=1.8 Hz, 1H), 7.19-6.86 (m,1H), 6.14 (s, 1H), 4.95-4.34 (m, 2H), 3.40-3.28 (m, 1H), 3.23-2.63 (m,2H), 1.92-1.75 (m, 2H), 1.64-1.42 (m, 14H).

(R)-1-{4-[2-(2-Chloro-4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A18”)

4-[2-(2-Chloro-4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-piperidine(110.0 mg; 0.334 mmol) and(R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (63.3 mg; 0.400mmol) were dissolved in DMF (2 mL) and the mixture was cooled in an icebath. HATU (190.3 mg; 0.500 mmol) and N-ethyldiisopropylamine (0.14 mL;0.834 mmol) were added, cooling was removed and the mixture was stirredfor 20 h at 25° C. The mixture was directly purified using preparativeHPLC (Agilent®, Column: Chromolith® prep 100-25). Pure fractions werelyophilized; yield: 34 mg (22%) off-white solid; (purity 100%, Rt: 2.29min, [M+H]⁺ 470-472); ¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.19 (d, J=1.3Hz, 1H), 7.93 (dd, J=8.2, 1.3 Hz, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.67 (d,J=1.8 Hz, 1H), 7.01 (s, 1H), 6.38 (s, 1H), 4.80-4.25 (m, 2H), 3.05-2.85(m, 1H), 2.68-2.50 (m, 2H), 1.81-1.66 (m, 2H), 1.60-1.40 (m, 5H).

(R)-1-{4-[2-(5-Bromo-pyrimidin-2-yl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A19”) 19.14-[2-(5-Bromo-pyrimidin-2-yl)-2H-pyrazol-3-yl]-piperidine-1-carboxylicacid tert-butyl ester

4-((E)-3-Dimethylamino-acryloyl)-piperidine-1-carboxylic acid tert-butylester (102.0 mg; 0.361 mmol) and 5-bromo-2-hydrazinopyrimidine (136.6mg; 0.722 mmol) were suspended in diethylene glycol dimethyl ether (4.0mL). The yellow suspension was heated in a microwave oven at 200° C. for65 min. The suspension was diluted with water and extracted with ethylacetate. The combined organic layers were washed with brine, dried withsodium sulfate, filtrated by suction and evaporated to dryness. Theresidue was purified by RP-chromatography; yield: 62 mg (42%) yellowoil.

19.2 5-Bromo-2-(5-piperidin-4-yl-pyrazol-1-yl)-pyrimidinedihydrochloride Preparation as described for “A32” (step 32.3) 19.3(R)-1-{4-[2-(5-Bromo-pyrimidin-2-yl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one

5-Bromo-2-(5-piperidin-4-yl-pyrazol-1-yl)-pyrimidine dihydrochloride(57.3 mg; 0.150 mmol) and(R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (47.4 mg; 0.300mmol) were dissolved in DMF (3 mL). N-Ethyldiisopropylamine (0.90 mL;5.292 mmol) and subsequently HATU (125.3 mg; 0.330 mmol) was added whilestirring. The suspension was stirred over night at room temperature. Thesolution was diluted with water and extracted with ethyl acetate. Thecombined organic layers were washed with water and brine, dried withsodium sulfate, filtrated by suction and evaporated to dryness. The oilyresidue was purified by preparative HPLC (Agilent®, Column: SunFire™Prep C18 OBD™ 5 μM; 30×150 mm). Pure fractions were lyophilized; yield:24 mg (36%) colorless solid; (purity 100%, Rt: 1.91 min, [M+H]⁺448-451); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 9.09 (s, 2H), 7.71 (d, J=1.7Hz, 1H), 7.07 (s, 1H), 6.48-6.40 (m, 1H), 4.96-4.32 (m, 2H), 3.67 (tt,J=11.7, 3.5 Hz, 1H), 3.18-2.57 (m, 2H), 2.04-1.86 (m, 2H), 1.68-1.35 (m,5H).

(R)-3,3,3-Trifluoro-2-hydroxy-1-(4-{2-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-2H-pyrazol-3-yl}-piperidin-1-yl)-2-methyl-propan-1-one(“A20”)

2-[4-(5-Piperidin-4-yl-pyrazol-1-yl)-phenyl]-propan-2-ol hydrochloride(92.7 mg; 0.288 mmol) and(R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (92.9 mg; 0.576mmol) were dissolved in DMF (5 mL) and and the mixture was cooled in anice bath. N-Ethyldiisopropylamine (0.35 mL; 2.016 mmol) and subsequentlyHATU (245.8 mg; 0.633 mmol) was added, cooling was removed and themixture was stirred room temperature for 14 h. The solution was dilutedwith water, rendered basic by addition of saturated sodium carbonatesolution and extracted with ethyl acetate. The combined organic layerswere washed with water and brine, dried with sodium sulfate, filtratedby suction and evaporated to dryness. The residue was purified bychromatography; yield: 28.5 mg (23%), colorless solid; (purity 100%, Rt:1.86 min, [M+H]⁺ 426); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.65-7.58 (m,2H), 7.55 (d, J=1.8 Hz, 1H), 7.42-7.35 (m, 2H), 7.02 (s, 1H), 6.32 (s,1H), 5.12 (s, 1H), 4.85-4.29 (m, 2H), 3.06-2.88 (m, 2H), 2.66-2.50 (m,1H), 1.89-1.74 (m, 2H), 1.62-1.39 (m, 11H).

(R)-1-{4-[2-(4-tert-Butyl-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A21”)

(R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (58.4 mg; 0.351mmol) and HATU (147.6 mg; 0.380 mmol) were dissolved in DMF (1 mL) andstirred at room temperature for 1 h. This solution was added to4-[2-(4-tert-Butyl-phenyl)-2H-pyrazol-3-yl]-piperidine hydrochloride(93.7 mg; 0.293 mmol) and N-ethyldiisopropylamine (0.13 ml; 0.732 mmol)dissolved in DMF (1 mL). The mixture was stirred at room temperature for14 h. (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-propionic acid (58.4 mg;0.351 mmol), HATU (147.6 mg; 0.380 mmol) and N-ethyldiisopropylamine(0.13 mL; 0.732 mmol) were dissolved in DMF (1 mL), stirred for 1 h andadded to the reaction mixture. After stirring the reaction mixture for 2h at room temperature another solution of(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-propionic acid (58.4 mg; 0.351mmol), HATU (147.6 mg; 0.380 mmol) and N-ethyldiisopropylamine (0.13 mL;0.732 mmol) in DMF (1 mL) was added. The reaction mixture was stirred atroom temperature for 2 h, diluted with water and extracted twice withethyl acetate. The combined organic layers were washed with brine, driedover sodium sulphate, filtered and concentrated in vacuo. The residuewas purified by flash chromatography (CombiFlashRF 200); yield: 82 mg(64%) colorless solid; (purity 97%, Rt: 2.34 min, [M+H]⁺ 424); ¹H NMR(400 MHz, DMSO-d₆) δ [ppm] 7.59-7.51 (m, 3H), 7.42-7.35 (m, 2H), 7.04(s, 1H), 6.32 (s, 1H), 4.84-4.27 (m, 2H), 3.07-2.89 (m, 2H), 2.65-2.49(m, 1H), 1.91-1.73 (m, 2H), 1.63-1.41 (m, 5H), 1.34 (s, 9H).

The following compounds were prepared as described for example “A21”.

(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[2-(4-isopropyl-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-methyl-propan-1-one(“A22”)

Yield: 87 mg (45%) colorless solid; (purity 96%, Rt: 2.36 min, [M+H]⁺410); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.55 (d, J=1.8 Hz, 1H),7.43-7.34 (m, 4H), 7.03 (s, 1H), 6.32 (s, 1H), 4.81-4.31 (m, 2H),3.05-2.90 (m, 3H), 2.69-2.48 (m, 1H), 1.86-1.74 (m, 2H), 1.57-1.45 (m,5H), 1.26 (d, J=6.9 Hz, 6H).

(R)-1-{4-[2-(4-Chloro-2-fluoro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one (“A23”)

Yield: 45 mg (15%) colorless solid; (purity 94%, Rt: 2.20 min, [M+H]⁺420-422); ¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 7.76 (dd, J=9.9, 2.3 Hz,1H), 7.64 (d, J=1.8 Hz, 1H), 7.62-7.57 (m, 1H), 7.51-7.46 (m, 1H), 7.01(s, 1H), 6.36 (s, 1H), 4.79-4.31 (m, 2H), 3.04-2.89 (m, 1H), 2.75-2.67(m, 1H), 2.62-2.49 (m, 1H), 1.79-1.68 (m, 2H), 1.59-1.42 (m, 5H).

(R)-1-{4-[2-(4-Ethyl-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A24”)

Yield: 56.5 mg (32%) colorless solid; (purity 97%, Rt: 2.26 min, [M+H]⁺396); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.55 (d, J=1.8 Hz, 1H),7.40-7.33 (m, 4H), 7.02 (s, 1H), 6.31 (s, 1H), 4.80-4.32 (m, 2H),3.05-2.89 (m, 2H), 2.70 (q, J=7.6 Hz, 2H), 2.64-2.52 (m, 1H), 1.86-1.72(m, 2H), 1.62-1.36 (m, 5H), 1.24 (t, J=7.6 Hz, 3H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(2-phenyl-2H-pyrazol-3-yl)piperidin-1-yl]-propan-1-one(“A25”)

Yield: 67 mg (27%) colorless solid; (purity 97%, Rt: 2.00 min, [M+H]⁺368); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.59-7.52 (m, 3H), 7.51-7.44 (m,3H), 7.04 (s, 1H), 6.33 (s, 1H), 4.83-4.26 (m, 2H), 3.05-2.88 (m, 2H),2.62-2.52 (m, 1H), 1.79 (t, J=13.3 Hz, 2H), 1.61-1.39 (m, 5H).

(R)-1-{4-[2-(2,4-Difluoro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A26”)

Yield: 60 mg (35%) colorless solid; (purity 97%, Rt: 2.06 min, [M+H]⁺404); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.67-7.53 (m, 3H), 7.33-7.25 (m,1H), 7.04 (s, 1H), 6.35 (s, 1H), 4.81-4.27 (m, 2H), 3.07-2.86 (m, 1H),2.73-2.62 (m, 1H), 2.62-2.49 (m, 1H), 1.78-1.65 (m, 2H), 1.59-1.39 (m,5H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-propan-1-one(“A27”)

To a solution of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid(90.3 mg; 0.571 mmol) in dichloromethane (0.5 mL)1-chloro-N,N,2-trimethyl-1-propenylamine (76.3 mg; 0.571 mmol) was addedand the solution was stirred at room temperature for 1.5 h. Thissolution was added slowly to a solution of4-[2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-piperidine (129.8 mg;0.439 mmol) and triethylamine (44.5 mg; 0.439 mmol) in dichloromethane(0.5 ml) and the resulting mixture was stirred at room temperature for1.5 h. The reaction mixture was diluted with water and extracted withdichloromethane. The combined organic layers were dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash chromatography (CombiFlashRF 200); yield: 40 mg (21%) colorlesssolid; (purity 100%, Rt: 2.29 min, [M+H]+ 436); ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 7.97-7.89 (m, 2H), 7.80-7.73 (m, 2H), 7.67 (d, J=1.8Hz, 1H), 7.06 (s, 1H), 6.43 (s, 1H), 4.84-4.34 (m, 2H), 3.17-2.90 (m,2H), 2.68-2.51 (m, 1H), 1.92-1.78 (m, 2H), 1.64-1.41 (m, 5H).

(R)-3,3,3-Trifluoro-1-{4-[2-(2-fluoro-4-methoxy-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A28”)

Preparation as described for example “A27”.

Yield: 70 mg (56%) colorless solid; (purity 100%, Rt: 2.06 min, [M+H]⁺416); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.57 (d, J=1.9 Hz, 1H), 7.43 (t,J=8.9 Hz, 1H), 7.09 (dd, J=12.1, 2.7 Hz, 1H), 7.02 (s, 1H), 6.95-6.90(m, 1H), 6.36-6.24 (m, 1H), 4.88-4.21 (m, 2H), 3.85 (s, 3H), 3.12-2.77(m, 1H), 2.71-2.60 (m, 1H), 2.59-2.44 (m, 1H), 1.82-1.65 (m, 2H),1.63-1.33 (m, 5H).

(R)-1-{4-[1-(5-Chloro-pyridin-2-yl)-1H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A29”) 29.1 4-(2H-Pyrazol-3-yl)-piperidine-1-carboxylic acid tert-butylester

4-((E)-3-Dimethylamino-acryloyl)-piperidine-1-carboxylic acid tert-butylester (220.0 mg; 0.779 mmol) was dissolved in ethanol (5.0 mL).Hydrazinium hydroxide (42 μL; 0.857 mmol) and triethylamine (120 μL;0.857 mmol) was added and the solution was stirred under reflux for 2hours. Another portion of hydrazinium hydroxide (42 μL; 0.857 mmol) wasadded and the yellow solution was refluxed for 1 h. The reaction mixturewas diluted with water and extracted with dichloromethane. The combinedorganic layers were dried over sodium sulfate, filtered and concentratedin vacuo; yield: 164 mg (84%) beige oil; (Rt: 1.91 min, (M+H-t-butyl196.1).

29.24-[1-(5-Chloro-pyridin-2-yl)-1H-pyrazol-3-yl]-piperidine-1-carboxylicacid tert-butyl ester

To a solution of 4-(2H-Pyrazol-3-yl)-piperidine-1-carboxylic acidtert-butyl ester (80.0 mg; 0.318 mmol) in DMF (2.0 mL) potassiumcarbonate (263.9 mg; 1.909 mmol) was added. 2,5-Dichloro-pyridine (56.5mg; 0.382 mmol) was added gradually over a period of 15 min and thereaction mixture was stirred at 110° C. overnight. The reaction mixturewas cooled to room temperature, diluted with water and extracted withethyl acetate. The combined organic layers were dried over sodiumsulfate, filtered and concentrated in vacuo; yield: 30 mg (26%) beigesolid.

29.3 4-[1-(5-Chloro-pyridin-2-yl)-1H-pyrazol-3-yl]-piperidinedihydrochloride Preparation as described for example “A32” (step 32.3)29.4(R)-1-{4-[2-(5-Chloro-pyridin-2-yl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one

Step 29.4 was prepared as described for example “A1”.

Purification by preparative HPLC (Agilent®, Column: SunFire™ Prep C18OBD™ 5 μM; 30×150 mm). Pure fractions were lyophilized; yield: 13 mg(41%), colorless solid; (purity 100%, Rt: 1.93 min, [M+H]⁺ 403-405); ¹HNMR (400 MHz, DMSO-d₆) δ[ppm] 8.53-8.45 (m, 2H), 8.06 (dd, J=8.8, 2.6Hz, 1H), 7.91-7.85 (m, 1H), 7.07 (s, 1H), 6.50 (d, J=2.6 Hz, 1H),4.86-4.32 (m, 2H), 3.28-3.09 (m, 1H), 3.06-2.95 (m, 1H), 2.91-2.73 (m,1H), 2.04-1.92 (m, 2H), 1.75-1.56 (m, 2H), 1.54 (s, 3H).

rac-3,3,3-Trifluoro-1-{4-[2-(2-fluoro-4-methoxy-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A30”)

“A30” was prepared as described for example “A1”.

Purification by RP-flash chromatography (CombiFlashRF 200); yield: 89 mg(27%) colorless solid; (purity 100%, Rt: 2.05 min, [M+H]⁺ 416);

¹H NMR (400 MHz, DMSO-d₆) δ 7.57 (d, J=1.9 Hz, 1H), 7.43 (t, J=8.9 Hz,1H), 7.09 (dd, J=12.1, 2.7 Hz, 1H), 7.02 (s, 1H), 6.95-6.90 (m, 1H),6.36-6.24 (m, 1H), 4.88-4.21 (m, 2H), 3.85 (s, 3H), 3.12-2.77 (m, 1H),2.71-2.60 (m, 1H), 2.59-2.44 (m, 1H), 1.82-1.65 (m, 2H), 1.63-1.33 (m,5H).

Example 31 Synthesis of(R)-1-{4-[2-(2,4-difluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A31”), diastereomeric mixture

31.1 1-(3-Methyl-pyridin-4-yl)-ethanone

A solution of methylmagnesiumchloride, (3.0 M in THF, 18.4 mL; 55.058mmol) was added slowly to a stirred solution ofN-methoxy-3,N-dimethylisonicotinamide (7.63 g; 42.352 mmol) in THF (200mL) at 0° C. under N₂ atmosphere and the mixture was stirred at roomtemperature for 1.5 h. The reaction was quenched under ice cooling with40 mL of saturated aqueous NH₄Cl-solution. The mixture was diluted withwater and extracted twice with ethyl acetate. The combined organiclayers were washed with brine, dried over sodium sulphate, filtered andconcentrated in vacuo. The oily residue was purified by flashchromatography (CombiFlashRF 200. yield: 5.29 g (92%) colorless solid;(purity 100%, Rt: 0.92 min).

31.2 (E)-3-Dimethylamino-1-(3-methyl-pyridin-4-yl)-propenone

1-(3-Methyl-pyridin-4-yl)-ethanone (1.10 g; 8.138 mmol) was dissolved inN,N-dimethylformamide dimethyl acetal (4.0 mL) in a microwave vessel andstirred at 80° C.) for 14 h. The reaction mixture was evaporated todryness and the residue (1.64 g) was used in the next step withoutfurther purification.

31.3 4-[2-(2,4-Difluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-pyridine

(E)-3-Dimethylamino-1-(3-methyl-pyridin-4-yl)-propenone (244.8 mg; 1.287mmol) and 2,4-difluorphylhydrazine hydrochloride (232.4 mg; 1.287 mmol)were dissolved in ethanol (5.0 mL) and refluxed for 2 h. The mixture wasevaporated to dryness and the residue purified by flash chromatography(CombiFlashRF 200); yield: 130 mg (37%) orange oil; (purity 100%, Rt:1.55 min, (M+H) 272.1).

31.4 4-[2-(2,4-Difluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidinehydrochloride

4-[2-(2,4-Difluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-pyridine (130.0 mg;0.479 mmol) was dissolved in ethanol (2 mL). Hydrochloric acid solution(1 M, 0.96 mL; 0.958 mmol) was added and the mixture was hydrogenatedwith platinum oxide hydrate at 5 bar and 50° C. for 14 h. The reactionmixture was filtered and concentrated in vacuo; yield: 138 mg (92%)beige solid;

31.5(R)-1-{4-[2-(2,4-Difluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one

Preparation as described for “A27”; yield: 82 mg (44%) colorless solid;mixture of diastereomers; (purity 98%, Rt: 2.13 min, (M+H) 418.2).

Synthesis of(R)-1-{(3R,4R)-4-[2-(2,4-difluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A32”)

and(R)-1-{(3S,4S)-4-[2-(2,4-difluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A33”)

32/33.14-[2-(2,4-Difluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidine-1-carboxylicacid tert-butyl ester

To a solution of4-[2-(2,4-difluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidinehydrochloride (357.00 mg; 1.138 mmol) and NaHCO₃ (286.7 mg; 3.413 mmol)in water (4.0 mL) di-tert-butyl dicarbonate (248.3 mg; 1.138 mmol),dissolved in dioxane (8.0 mL) was added and the resulting mixture wasstirred at room temperature for 18 h. The reaction mixture was dilutedwith water and saturated aqueous NaHCO₃-solution, extracted withdichloromethane. The combined organic layers were dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash chromatography (CombiFlashRF 200; yield: 305 mg (71%) colorlessoil; mixture of diastereomers; (purity 100%, Rt: 2.51 min, (M+H) 378.2).

32/33.2(3R,4R)-4-[2-(2,4-Difluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidine-1-carboxylicacid tert-butyl ester and(3S,4S)-4-[2-(2,4-difluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidine-1-carboxylicacid tert-butyl ester

The diastereomers were separated by chiral chromatography (column:Chiralpak AD-H, solvent: CO₂+5% MeOH).

Yield (32.2): 79.8 mg (26%) colorless oil; HPLC (Chiralpak AD-H;CO₂/MeOH-95/5): Rt 2.08 min;

Yield (33.2): 75 mg (25%) colorless oil; HPLC (Chiralpak AD-H;CO₂/MeOH-95/5): Rt 2.37 min.

32.3(3R,4R)-4-[2-(2,4-Difluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidinehydrochloride

Hydrogen chloride solution (4.0 M in dioxane; 3.0 mL) was added to(3R,4R)-4-[2-(2,4-difluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidine-1-carboxylicacid tert-butyl ester (79.0 mg; 0.209 mmol) dissolved in dioxane (3.0mL) and stirred over night at ambient temperature. The reaction wasconcentrated in vacuo. The residue was used in the next step withoutfurther purification.

32.4(R)-1-{(3R,4R)-4-[2-(2,4-Difluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one

(3R,4R)-4-[2-(2,4-Difluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidinehydrochloride (65.6 mg; 0.209 mmol),(R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (42.9 mg; 0.272mmol) and HATU (119.2 mg; 0.314 mmol) were dissolved in DMF (8.0 mL).N-ethyldiisopropylamine (243.1 mg; 1.881 mmol) was added and the mixturewas stirred at room temperature over night. The mixture was evaporatedto dryness and the residue was purified by RP-flash chromatography(CombiFlashRF 200); yield: 86 mg (99%) colorless solid; (purity 100%,Rt: 2.1 min, (M+H) 418.2); HPLC (Chiralpak AD-H; CO₂/MeOH-95/5): Rt 3.84min; ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.64-7.59 (m, 1H), 7.59-7.50 (m,1H), 7.49-7.41 (m, 1H), 7.27-7.19 (m, 1H), 6.79-6.72 (m, 1H), 6.35-6.27(m, 1H), 4.67-4.33 (m, 1H), 4.08-4.00 (m, 1H), 3.22-3.13 (m, 1H),3.02-2.89 (m, 2H), 1.99-1.84 (m, 1H), 1.76-1.63 (m, 2H), 1.61-1.43 (m,3H), 0.66-0.59 (m, 3H).

33.3(3S,4S)-4-[2-(2,4-Difluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidinehydrochloride

Preparation as described for example “A32” (step 32.3).

33.4(R)-1-{(3S,4S)-4-[2-(2,4-Difluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one

Preparation and purification as described for example “A32” (step 32.4);yield: 73 mg (88%) colorless solid; (purity 100%, Rt: 2.1 min, (M+H)418.2); HPLC (Chiralpak AD-H; CO₂/MeOH-95/5): Rt 4.65 min; ¹H NMR (400MHz, DMSO-d₆) δ [ppm] 7.64-7.59 (m, 1H), 7.59-7.52 (m, 1H), 7.51-7.40(m, 1H), 7.28-7.19 (m, 1H), 6.76 (s, 1H), 6.34-6.26 (m, 1H), 4.60-4.32(m, 1H), 4.16-3.98 (m, 1H), 3.20-3.09 (m, 1H), 3.01-2.85 (m, 2H),1.96-1.83 (m, 1H), 1.77-1.61 (m, 2H), 1.57-1.49 (m, 3H), 0.67-0.56 (m,3H).

Example 34

(R)-1-{4-[1-(4-Chloro-phenyl)-5-methyl-1H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A34”) 34.1 4-(5-Methyl-2H-pyrazol-3-yl)-pyridine

1-(4-Pyridinyl)-1,3-butanedione (815.0 mg; 4.995 mmol) was suspended inethanol (6.0 mL), hydrazinium hydroxide (242.8 μl; 4.995 mmol) was addedand the mixture was stirred at 85° C. for 48 h. The reaction mixture wasdiluted with and saturated NaHCO₃-solution (pH 7-8) and extracted withdichloromethane. The combined organic layers were dried over sodiumsulfate, filtered and concentrated in vacuo; yield: 703 mg (88%) beigesolid.

34.2 4-(5-Methyl-2H-pyrazol-3-yl)-piperidine hydrochloride

4-(5-Methyl-2H-pyrazol-3-yl)-piperidine hydrochloride (689.0 mg; 4.328mmol) was dissolved in ethanol (10 mL). Hydrochloric acid solution (1 M,8.7 mL; 8.656 mmol) was added and the mixture was hydrogenated withplatinum oxide hydrate (80% Pt, 100.0 mg) at atmospheric pressure androom temperature for 14 h. The reaction mixture was filtered andconcentrated in vacuo; yield: 873 mg (100%) yellow solid.

34.3 4-(5-Methyl-2H-pyrazol-3-yl)-piperidine-1-carboxylic acidtert-butyl ester

4-(5-Methyl-2H-pyrazol-3-yl)-piperidine hydrochloride (827.9 mg; 4.105mmol) was dissolved in water (14.0 mL). NaHCO₃ (1.03 g; 12.315 mmol) anddi-tert-butyldicarbonate (895.9 mg; 4.105 mmol) dissolved in dioxane(26.0 mL) were added and the mixture was stirred for 14 h at roomtemperature. The reaction mixture was diluted with water and extractedwith dichloromethane. The combined organic layers were dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash chromatography (CombiFlashRF 200); yield: 1.013 g (93%) colorlesssolid; Rt: 1.88 min, (M+H-t-butyl) 210.2).

34.44-[1-(4-Chloro-phenyl)-5-methyl-1H-pyrazol-3-yl]-piperidine-1-carboxylicacid tert-butyl ester

4-(5-Methyl-2H-pyrazol-3-yl)-piperidine-1-carboxylic acid tert-butylester (247.6 mg; 0.933 mmol), 4-chlorophenylboronic acid (291.8 mg;1.866 mmol), anhydrous copper acetate (254.2 mg; 1.399 mmol) and alittle amount of molecular sieves 4 Å was suspended in dichloromethane(8.0 mL). Pyridine (147.6 mg; 1.866 mmol) was added and the mixture wasstirred at ambient temperature over night. The reaction mixture wasevaporated to dryness and the residue was purified by RP-chromatography(CombiFlashRF 200); yield: 318 mg (91%) yellow oil; Rt: 2.79 min, (M+H)376.2-378.2.

34.5 4-[1-(4-Chloro-phenyl)-5-methyl-1H-pyrazol-3-yl]-piperidinehydrochloride

Hydrogen chloride solution (4.0 M in dioxane; 4.0 mL) was added to4-[2-(4-Chloro-phenyl)-5-methyl-2H-pyrazol-3-yl]-piperidine-1-carboxylicacid tert-butyl ester (318.4 mg; 0.847 mmol) in dioxane (4.0 m) andstirred for 14 h at ambient temperature. The reaction was concentratedin vacuo; yield: 264 mg (100%).

34.6(R)-1-{4-[1-(4-Chloro-phenyl)-5-methyl-1H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A34”)

The acylation reaction was performed as described for example “A27”.Purification by RP-flash chromatography (CombiFlashRF 200).

Yield: 62 mg (46%) colorless solid; (purity 100%, Rt: 2.38 min, (M+H)416.1-418.2); ¹H NMR (400 MHz, DMSO-d₆) δ 7.64-7.56 (m, 4H), 7.08 (s,1H), 6.23 (s, 1H), 4.94-4.28 (m, 2H), 3.31-3.02 (m, 1H), 3.02-2.71 (m,2H), 2.37 (s, 3H), 2.06-1.92 (m, 2H), 1.79-1.46 (m, 5H).

Example 35

(R)-1-{4-[2-(4-Chloro-phenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A35”) 35.1 4-(5-Trifluoromethyl-2H-pyrazol-3-yl)-piperidinehydrochloride

4-(5-Trifluoromethyl-2H-pyrazol-3-yl)-pyridine (619.0 mg; 2.904 mmol)was dissolved in ethanol (10 mL). Hydrochloric acid solution (1 M, 5.8mL; 5.808 mmol) was added and the mixture was hydrogenated with platinumoxide hydrate (80% Pt, 100.0 mg) at atmospheric pressure and roomtemperature over night. The reaction mixture was filtered andconcentrated in vacuo; yield: 817 mg (100%) light yellow solid.

35.2 4-(5-Trifluoromethyl-2H-pyrazol-3-yl)-piperidine-1-carboxylic acidtert-butyl ester

4-(5-Trifluoromethyl-2H-pyrazol-3-yl)-piperidine hydrochloride (752.0mg; 2.940 mmol) was dissolved in water (14.0 mL). NaHCO₃ (741.0 mg;8.820 mmol) and di-tert-butyldicarbonate (641.6 mg; 2.940 mmol),dissolved in dioxane (26.0 mL), were added and the mixture stirred for14 h at room temperature. The reaction mixture was diluted with waterand extracted with dichloromethane. The combined organic layers weredried over sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by flash chromatography (CombiFlashRF 200); yield:806 mg (86%) colorless solid; (purity 100%, Rt: 2.33 min, (M+H-t-butyl)264.1).

35.34-[2-(4-Chloro-phenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-piperidine-1-carboxylicacid tert-butyl ester

4-(5-Trifluoromethyl-2H-pyrazol-3-yl)-piperidine-1-carboxylic acidtert-butyl ester (260.0 mg; 0.814 mmol), 4-chlorophenylboronic acid(254.6 mg; 1.628 mmol), anhydrous copper acetate (221.8 mg; 1.221 mmol)and a little amount of molecular sieves 4 Å was suspended indichloromethane (8.0 mL). Pyridine (128.8 mg; 1.628 mmol) was added andthe reaction was stirred for 48 h at ambient temperature. The reactionmixture was evaporated to dryness and the residue was purified byRP-chromatography (CombiFlashRF 200); yield: 333 mg (95%) colorless oil;Rt: 2.90 min, (M+H) 430.2-432.1.

35.44-[2-(4-Chloro-phenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-piperidinehydrochloride

Preparation as described for example “A34” (step 34.5).

35.5(R)-1-{4-[2-(4-Chloro-phenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A35”)

The acylation reaction was performed as described for example 27;purification by RP-flash chromatography (CombiFlashRF 200); yield: 56 mg(37%) colorless solid; (purity 100%, Rt: 2.54 min, (M+H) 470.1-472.1);¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.69-7.63 (m, 2H), 7.63-7.58 (m, 2H),7.05-6.96 (m, 1H), 6.95-6.81 (m, 1H), 4.89-4.25 (m, 2H), 3.03-2.89 (m,2H), 2.59 (s, 1H), 1.90-1.73 (m, 2H), 1.71-1.41 (m, 5H).

(R)-1-[4-(2-Isopropyl-2H-pyrazol-3-yl)-piperidin-1-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A36”)

Preparation and purification as described for example “A17”; yield: 186mg (9%), brown solid; (purity 96%, Rt: 2.99 min); ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 7.32 (d, J=1.6 Hz, 1H), 7.07 (s, 1H), 5.98 (s, 1H),4.80-4.78 (m, 1H), 4.60-4.54 (m, 1H), 4.47-4.40 (m, 1H), 3.14-3.12 (m,1H), 3.02-3.00 (m, 1H), 2.73-2.71 (m, 1H), 1.87-1.85 (m, 2H), 1.55-1.45(m, 5H), 1.36 (d, J=6.48 Hz, 6H).

(R)-1-[4-(2-Cyclohexyl-2H-pyrazol-3-yl)-piperidin-1-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A37”)

Preparation and purification as described for example “A17”; yield: 142mg (9%), off-white solid; (purity 99%, Rt: 3.92 min);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.30 (d, J=1.7 Hz, 1H), 7.07 (s, 1H),5.98 (s, 1H), 4.81-4.79 (m, 1H), 4.46-4.44 (m, 1H), 4.16-4.10 (m, 1H),3.12-3.10 (m, 1H), 3.06-3.03 (m, 1H), 2.76-2.74 (m, 1H), 1.84-1.64 (m,10H), 1.52 (s, 3H), 1.48-1.39 (m, 3H), 1.22-1.16 (m, 1H).

(R)-1-[4-(2-Benzyl-2H-pyrazol-3-yl)-piperidin-1-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A38”)

Preparation and purification as described for example “A17”; yield: 7 mg(1%), (purity 95.7%, Rt: 5.36 min); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]7.52 (d, J=1.7 Hz, 1H), 7.35-7.27 (m, 3H), 7.05 (d, J=6.9 Hz, 2H), 6.10(d, J=1.8 Hz, 1H), 5.38 (s, 2H), 5.31-5.29 (m, 1H), 4.44-4.42 (m, 2H),2.89-2.78 (m, 3H), 1.78-1.76 (m, 2H), 1.63-1.60 (m, 3H), 1.59-1.50 (m,2H).

(R)-1-{4-[2-(2-Chloro-4-fluoro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A39”)

Preparation as described for example 1; yield: 187 mg (29%), (purity99.1%, Rt: 4.18 min); ¹H NMR (400 MHz, DMSO-d₆): □ [ppm] 7.76-7.73 (m,1H), 7.67-7.63 (m, 1H), 7.60 (s, 1H), 7.44-7.40 (m, 1H), 7.04 (s, 1H),6.33 (br s, 1H), 4.68-4.65 (m, 1H), 4.35-4.33 (m, 1H), 2.95-2.93 (m,1H), 2.49-2.47 (m, 2H), 1.73-1.71 (m, 2H), 1.49-1.35 (m, 5H).

(R)-1-{4-[1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A40”)

(R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A41”)

Examples “A40” and “A41” were prepared as described for example “A34”.Purification by RP-flash chromatography (CombiFlashRF 200). Separationof the obtained regioisomers by preparative HPLC (Agilent®, Column:Chromolith® SpeedROD RP18e 50-4.6); example “A40”, yield: 33 mg (19%)colorless solid; (purity 100%, Rt: 2.23 min, (M+H) 400.1);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.56-7.49 (m, 2H), 7.37-7.28 (m, 2H),7.01 (s, 1H), 6.14 (s, 1H), 4.81-4.28 (m, 2H), 3.23-3.06 (m, 1H),2.93-2.70 (m, 2H), 2.28 (s, 3H), 1.99-1.86 (m, 2H), 1.69-1.43 (m, 5H);example “A41”, yield: 12 mg (7%) colorless solid; (purity 100%, Rt: 2.09min, (M+H) 400.1); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.52-7.44 (m, 2H),7.39-7.30 (m, 2H), 7.03 (s, 1H), 6.11 (s, 1H), 4.84-4.23 (m, 2H),3.04-2.80 (m, 2H), 2.65-2.46 (m, 1H), 2.17 (s, 3H), 1.86-1.68 (m, 2H),1.63-1.32 (m, 5H).

(R)-1-{4-[2-(4-Fluoro-phenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A42”)

Example “A42” was prepared as described for example “A35”.

Purification by RP-flash chromatography (CombiFlashRF 200); yield: 71 mg(50%) colorless solid; (purity 100%, Rt: 2.43 min, (M+H) 454.1); ¹H NMR(400 MHz, DMSO-d₆) δ [ppm] 7.66-7.58 (m, 2H), 7.47-7.39 (m, 2H),7.07-6.95 (m, 1H), 6.93-6.77 (m, 1H), 2.70-2.52 (m, 1H), 4.88-4.25 (m,2H), 3.07-2.84 (m, 2H), 1.90-1.72 (m, 2H), 1.69-1.40 (m, 5H).

(R)-1-[4-(2-Phenyl-5-trifluoromethyl-2H-pyrazol-3-yl)-piperidin-1-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A43”)

Example “A43” was prepared as described for example “A35”.

Purification by RP-flash chromatography (CombiFlashRF 200); yield: 104mg (55%) colorless solid; (purity 100%, Rt: 2.39 min, (M+H) 436.2); ¹HNMR (400 MHz, DMSO-d₆) δ [ppm] 7.66-7.50 (m, 5H), 7.06-6.96 (m, 1H),6.94-6.79 (m, 1H), 4.87-4.24 (m, 2H), 3.06-2.52 (m, 3H), 1.89-1.73 (m,2H), 1.70-1.40 (m, 5H).

(R)-1-{4-[1-(4-Fluoro-phenyl)-1H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A44”) 44.1 3-Methyl-4-(2H-pyrazol-3-yl)-pyridine

(E)-3-Dimethylamino-1-(3-methyl-pyridin-4-yl)-propenone (preparation seeexample 31.2; 1.46 g; 7.634 mmol) was dissolved in ethanol (12.0 mL).

Hydrazinium hydroxide (371 μl; 7.634 mmol) was added and the mixture wasstirred at 85° C. for 48 h. The reaction mixture was diluted with waterand saturated NaHCO₃-solution (pH 7-8) and extracted withdichloromethane. The combined organic layers were dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash chromatography (CombiFlashRF 200); yield: 804 mg (66%) yellow oil.

44.2 3-Methyl-4-(2H-pyrazol-3-yl)-piperidine hydrochloride

Hydrogenation reaction as described for example 34.2 (5 bar, roomtemperature, 4 h); yield: 876 mg (100%) colorless oil.

44.3 3-Methyl-4-(2H-pyrazol-3-yl)-piperidine-1-carboxylic acidtert-butyl ester

BOC-protection as described for example 34.3; yield: 750 mg (66%)colorless oil; Rt: 1.98 min, (M+H-t-butyl) 210.1).

44.44-[1-(4-Fluoro-phenyl)-1H-pyrazol-3-yl]-3-methyl-piperidine-1-carboxylicacid tert-butyl ester

The arylation reaction and purification was performed as described forexample 34.4; yield: 376 mg (79%) light yellow oil; Rt: 2.79 min,(M+H-t-butyl) 304.2.

44.5 4-[1-(4-Fluoro-phenyl)-1H-pyrazol-3-yl]-3-methyl-piperidinehydrochloride

Deprotection was peformed as described for example 34.5; yield: 309 mg(100%).

44.6(R)-1-{4-[1-(4-Fluoro-phenyl)-1H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A44”)

The acylation reaction was performed as described for example 27; yield:409 mg (89%) colorless solid; mixture of diastereoisomers; (purity98.5%, Rt: 2.36 min, (M+H) 400.2).

The following compounds have been prepared analogously:

(R)-3,3,3-Trifluoro-1-{(3R,4R)-4-[1-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A45”)

(R)-3,3,3-Trifluoro-1-{(3S,4S)-4-[1-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A46”)

“A44” was separated in the single diastereomers by chiral chromatography(Column: Chiralpak AD-H, solvent: CO₂+10% MeOH+0.5% diethylamine).

Yield (“A45”): 100 mg (25%) colorless oil; (purity 100%, Rt: 2.36 min,(M+H) 400.2); HPLC (Chiralpak AD-H; CO₂/MeOH/diethylamine-95/5/0.5): Rt3.83 min; ¹H NMR (500 MHz, DMSO-d₆) S [ppm] 8.44 (d, J=2.5 Hz, 1H),7.94-7.84 (m, 2H), 7.44-7.34 (m, 2H), 7.25-6.95 (m, 1H), 6.46 (d, J=2.5Hz, 1H), 4.87-3.77 (m, 2H), 3.47-3.40 (m, 1H), 3.28-3.04 (m, 2H),2.34-2.15 (m, 1H), 2.15-1.94 (m, 1H), 1.94-1.83 (m, 1H), 1.63 (s, 3H),0.88-0.63 (m, 3H).

Yield (“A46”): 122 mg (30%) colorless oil; (purity 98.5%, Rt: 2.35 min,(M+H) 400.2); HPLC (Chiralpak AD-H; CO₂/MeOH-95/5): Rt 5.61 min;

¹H NMR (400 MHz, DMSO-d₆) [ppm] 8.37 (d, J=2.5 Hz, 1H), 7.88-7.78 (m,2H), 7.36-7.26 (m, 2H), 7.02 (s, 1H), 6.38 (d, J=2.5 Hz, 1H), 4.81-3.55(m, 2H), 3.44-3.21 (m, 1H), 3.21-3.04 (m, 2H), 2.27-2.10 (m, 1H),2.02-1.85 (m, 1H), 1.85-1.71 (m, 1H), 1.55 (s, 3H), 0.84-0.56 (m, 3H).

(R)-1-[4-(5-Methyl-1-phenyl-1H-pyrazol-3-yl)-piperidin-1-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A47”)

“A47” was prepared as described for example “A34”.

Purification by RP-flash chromatography (CombiFlashRF 200); yield: 8 mg(12%) colorless solid; (purity 100%, Rt: 2.20 min, (M+H) 382.2);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.53-7.46 (m, 4H), 7.42-7.35 (m, 2H),7.03 (s, 1H), 6.14 (s, 1H), 4.81-4.29 (m, 2H), 3.19-3.04 (m, 1H),2.95-2.67 (m, 2H), 2.30 (s, 3H), 2.00-1.87 (m, 2H), 1.64-1.42 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[2-(3-chloro-4-methoxy-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-methyl-propan-1-one(“A48”)

Preparation according to the procedure described for example “A1”;yield: 188 mg (62%), colorless solid; (purity: 99%, Rt: 2.14 min, (M+H)432.1-434.1);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.54 (d, J=2.2 Hz, 2H), 7.42 (dd,J=8.8, 2.6 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H), 7.00 (s, 1H), 6.33-6.26 (m,1H), 4.83-4.28 (m, 2H), 3.94 (s, 3H), 3.06-2.82 (m, 2H), 2.69-2.51 (m,1H), 1.87-1.70 (m, 2H), 1.62-1.35 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-(4-{2-[4-(2,2,2-trifluoro-ethoxy)phenyl]-2H-pyrazol-3-yl}-piperidin-1-yl)-propan-1-one(“A49”)

Preparation according to the procedure described for example “A1”;yield: 251 mg (64%), colorless solid; (purity: 99%, Rt: 2.24 min, (M+H)466.2);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.54 (d, J=1.8 Hz, 1H), 7.46-7.40 (m,2H), 7.24-7.16 (m, 2H), 7.00 (s, 1H), 6.33-6.26 (m, 1H), 4.85 (q, J=8.8Hz, 2H), 4.80-4.27 (m, 2H), 3.03-2.84 (m, 2H), 2.68-2.51 (m, 1H),1.86-1.70 (m, 2H), 1.62-1.38 (m, 5H).

(R)-1-{4-[2-(4-Chloro-phenyl)-5-methyl-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A50”) 50.1 4-[2-(4-Chloro-phenyl)-5-methyl-2H-pyrazol-3-yl]-piperidine

4-(3-Oxo-butyryl)-piperidine-1-carboxylic acid tert-butyl ester (192.0mg; 0.713 mmol) and 4-chlorophenylhydrazine hydrochloride (140.4 mg;0.784 mmol) was dissolved in ethanol (5.0 mL) and the solution washeated to reflux for 3 h. The mixture was cooled to room temperature andevaporated under reduced pressure. The crude residue was purified byflash chromatography (CombiFlashRF 200).

Yield: 38 mg (14%) yellow oil,4-[1-(4-chloro-phenyl)-5-methyl-1H-pyrazol-3-yl]-piperidine-1-carboxylicacid tert-butyl ester;

Yield: 24 mg (12%) yellow oil (12%),4-[2-(4-chloro-phenyl)-5-methyl-2H-pyrazol-3-yl]-piperidine;

Yield: 140 mg (69%) yellow oil/solid (crystallized upon standing)

50.2(R)-1-{4-[2-(4-Chloro-phenyl)-5-methyl-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A50”)

The acylation reaction was performed as described for example “A1”.

Purification by RP-flash chromatography (CombiFlashRF 200).

Yield: 136 mg (67%) colorless solid; (purity 99.5%, Rt: 2.22 min, (M+H)416.2-418.1);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.60-7.54 (m, 2H), 7.50-7.45 (m, 2H),7.01 (s, 1H), 6.13 (s, 1H), 4.85-4.29 (m, 2H), 3.04-2.88 (m, 2H),2.66-2.51 (m, 1H), 2.18 (s, 3H), 1.87-1.73 (m, 2H), 1.61-1.36 (m, 5H).

(R)-1-[4-(2-Cyclopentyl-2H-pyrazol-3-yl)-piperidin-1-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A51”)

Preparation and purification as described for example “A17”.

Yield: 55 mg (11%), colorless solid; (purity 99.1%, Rt: 3.73 min);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.32 (d, J=1.5 Hz, 1H), 7.07 (s, 1H),5.99 (s, 1H), 4.76-4.71 (m, 1H), 4.46-4.44 (m, 1H), 3.06-3.00 (m, 2H),2.73-2.71 (m, 1H), 2.00-1.98 (m, 2H), 1.90-1.84 (m, 7H), 1.61-1.58 (m,2H), 1.52-1.35 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(2-methyl-2H-pyrazol-3-yl)piperidin-1-yl]-propan-1-one(“A52”)

Preparation and purification as described for example “A17”.

Yield: 98 mg (11%), brown solid; (purity 99.5%, Rt: 2.45 min);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.27 (d, J=1.8 Hz, 1H), 7.08 (s, 1H),6.03 (s, 1H), 4.79-4.78 (m, 1H), 4.46-4.44 (m, 1H), 3.77 (s, 3H),3.24-3.18 (m, 1H), 3.00-2.98 (m, 1H), 2.69-2.67 (m, 1H), 1.89-1.87 (m,2H), 1.63-1.30 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[2-(6-methoxy-pyridin-3-yl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-methyl-propan-1-one(“A53”)

Preparation and purification as described for example “A17”.

Yield: 15 mg (8%), colorless solid; (purity 98%, Rt: 3.54 min);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 8.22 (d, J=2.0 Hz, 1H), 7.68-7.66 (m,2H), 6.91 (d, J=8.7 Hz, 1H), 6.25 (s, 1H), 5.13-5.11 (m, 1H), 4.49-4.47(m, 2H), 4.03 (s, 3H), 2.90-2.81 (m, 3H), 1.91-1.80 (m, 2H), 1.72-1.62(m, 5H).

5-(2-Fluoro-phenyl)-4-[1-((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionyl)piperidin-4-yl]-2,4-dihydro-[1,2,4]triazol-3-one(“A54”) 54.1 N-(1-Benzyl-piperidin-4-yl)-2-fluoro-benzamide

4-Amino-N-benzylpiperidine (0.87 mL; 4.613 mmol) andN-ethyldiisopropylamine (1.43 mL; 8.388 mmol) were dissolved indichloromethane (2 mL). This solution was added dropwise to a solutionof 2-fluorbenzoylchlorid (0.50 mL; 4.194 mmol) dissolved indichloromethane (2 mL) and the mixture was stirred at 25° C. for 1 h.The mixture was diluted with dichloromethane and extracted with 1N HCl,washed with 2N NaOH and water. The organic phase was dried over MgSO₄and concentrated under reduced pressure. The product was used in thenext step without further purification; yield: 1.04 g (79%).

54.2N′-[1-(1-Benzyl-piperidin-4-ylamino)-1-(2-fluoro-phenyl)-meth-(E)-ylidene]-hydrazinecarboxylicacid tert-butyl ester

N-(1-Benzyl-piperidin-4-yl)-2-fluoro-benzamide (1.040 g; 3.329 mmol) wasdissolved in toluene (20.0 mL) and phosphorus pentachloride (832.0 mg;3.995 mmol) was added under nitrogen. The mixture was refluxed at 130°C. for 4 h. The solvent was removed and the residue dissolved in dry THF(40.0 mL). This solution was added dropwise to a solution ofhydrazinecarboxylic acid tert-butyl ester (792.0 mg; 5.993 mmol) in dryTHF (40.0 mL) at 0° C. After complete addition the mixture was stirredat 25° C. for 14 h. The reaction mixture was evaporated to dryness andthe residue was used in the next step without further purification;yield: 808 mg (57%).

54.3 N′-amino-N-(1-benzyl-4-piperidyl)-2-fluoro-benzamidine

N′-[1-(1-Benzyl-piperidin-4-ylamino)-1-(2-fluoro-phenyl)-meth-(E)-ylidene]-hydrazinecarboxylicacid tert-butyl ester (808.0 mg; 1.894 mmol) was dissolved in HClsolution (4.0 M in dioxane; 20.0 mL) and stirred at 25° C. for 20 h. Themixture was concentrated under reduced pressure and extracted with ethylacetate. The combined organic phases were washed with 2 N sodiumhydroxide solution, dried over magnesium sulfate, filtered andevaporated to dryness. The residue was used in the next step withoutfurther purification; yield: 600 mg (97%).

54.44-(1-Benzyl-piperidin-4-yl)-5-(2-fluoro-phenyl)-2,4-dihydro-[1,2,4]triazol-3-one

1,1′-Carbonyldiimidazole (124.9 mg; 0,770 mmol) was dissolved in THF (80mL) and warmed to 50° C.N′-amino-N-(1-benzyl-4-piperidyl)-2-fluoro-benzamidine (200.0 mg; 0,613mmol) was dissolved in THF (50 mL) and added dropwise over 2 h. Afterthat the reaction mixture was stirred for 1 h without heating. Themixture was diluted with dichloromethane and extracted with 1N NaOH andwater, dried over magnesium sulfate and concentrated under reducedpressure; yield: 30 mg (14%).

54.55-(2-Fluoro-phenyl)-4-piperidin-4-yl-2,4-dihydro-[1,2,4]triazol-3-one

4-(1-Benzyl-piperidin-4-yl)-5-(2-fluoro-phenyl)-2,4-dihydro-[1,2,4]triazol-3-one(50.0 mg; 0.142 mmol) was dissolved in THF (10 mL) and hydrogenated overPd/C at normal pressure and room temperature for 14 h. The reactionmixture was evaporated under reduced pressure and the residue used inthe next step without further purification; yield: 35 mg (94%).

54.65-(2-Fluoro-phenyl)-4-[1-((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-2,4-dihydro-[1,2,4]triazol-3-one(“A54”)

5-(2-Fluoro-phenyl)-4-piperidin-4-yl-2,4-dihydro-[1,2,4]triazol-3-one(35.0 mg; 0.133 mmol) and(R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (25.3 mg; 0.160mmol) were dissolved in DMF (1.0 mL) and the mixture was cooled in anice bath. HATU (76.1 mg; 0.200 mmol) and N-ethyldiisopropylamine (0.06ml; 0.334 mmol) were added, cooling was removed and the mixture wasstirred at 25° C. for 20 h. The reaction was evaporated and the residuepurified by RP-flash-chromatography; yield: 10 mg (18%) off-white solid;(purity: 100%, Rt: 1.73 min, (M+H) 403.1);

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 12.01 (s, 1H), 7.69-7.63 (m, 1H), 7.57(td, J=7.5, 1.8 Hz, 1H), 7.47-7.40 (m, 1H), 7.38 (td, J=7.5, 1.1 Hz,1H), 7.08 (s, 1H), 4.89-4.35 (m, 2H), 3.79-3.68 (m, 1H), 3.17-3.03 (m,1H), 2.99-2.85 (m, 1H), 2.60-2.54 (m, 1H), 2.36-2.09 (m, 1H), 1.77-1.63(m, 2H), 1.48 (s, 3H).

(R)-3,3,3-Trifluoro-1-{4-[3-(2-fluoro-phenyl)-[1,2,4]triazol-4-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A55”) 55.11-Benzyl-4-[3-(2-fluoro-phenyl)-[1,2,4]triazol-4-yl]-piperidine

Toluene-4-sulfonic acid monohydrate (61.1 mg; 0.355 mmol) anddimethoxymethyl-dimethyl-amine (0.54 mL; 4.068 mmol) were added to asolution of N′-amino-N-(1-benzyl-4-piperidyl)-2-fluoro-benzamidine (1.0g; 3.064 mmol) in dry toluene (0.35 mL). The reaction mixture wasrefluxed for 14 h using a Dean-Stark-apparatus and evaporated todryness. The residue was dissolved in ethyl acetate, washed with sodiumcarbonate solution and water, dried over magnesium sulfate andconcentrated in vacuo. The oily residue was purified byRP-chromatography; yield: 250 mg (24%).

55.2 4-[3-(2-Fluoro-phenyl)-1,2,4-triazol-4-yl]-piperidine

Hydrogenation as described for example 54 (step 54.5). The product wasused in the next step without further purification; yield: 150 mg (82%).

55.3(R)-3,3,3-Trifluoro-1-{4-[3-(2-fluoro-phenyl)-[1,2,4]triazol-4-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A55”)

The acylation reaction was performed as described for example 54 (step54.6); Purification RP-flash-chromatography; yield: 23 mg (10%)colorless solid; (purity: 100%, Rt: 1.68 min, (M+H) 387.1);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 8.91 (s, 1H), 7.71-7.64 (m, 1H), 7.59(td, J=7.5, 1.8 Hz, 1H), 7.49-7.38 (m, 2H), 7.06 (s, 1H), 4.89-4.36 (m,2H), 4.13-4.00 (m, 1H), 3.13-2.57 (m, 2H), 2.01-1.77 (m, 4H), 1.54 (s,3H).

(R)-1-{4-[3-(4-Chloro-phenyl)-[1,2,4]triazol-4-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A56”) 56.1 4-(4-Chloro-benzoylamino)-piperidine-1-carboxylic acidethyl ester

4-Amino-piperidine-1-carboxylic acid ethyl ester (738.0 mg; 4.285 mmol)was dissolved in dry dichloromethane (7.5 mL) and 4-chlorobenzoylchloride (0.551 mL; 4.285 mmol) was added dropwise over a period of 5min. The temperature increased during the addition from room temperatureto 35° C. and a pale brown precipitate was formed. The reaction mixturewas stirred for 1.5 h at ambient temperature. The reaction mixture wasdiluted with dichloromethane and washed with saturated NaHCO₃ solutionand brine, dried with sodium sulfate, filtered by suction and evaporatedto dryness. The solid residue was triturated with diethyl ether,filtered by suction, washed with diethyl ether and dried; yield: 929 mg(70%); (purity: 98.2%, Rt: 2.02 min, (M+H) 311.1).

The following steps (56.2-56.4) were performed as described for example“A54” (step 54.2-54.3) and example “A55” (step 55.1).

56.5 4-[3-(4-Chloro-phenyl)-[1,2,4]triazol-4-yl]-piperidine

4-[3-(4-Chloro-phenyl)-[1,2,4]triazol-4-yl]-piperidine-1-carboxylic acidethyl ester (305.0 mg; 0.911 mmol) was dissolved in chloroform (7.5 mL)and iodotrimethylsilane (0.248 ml; 1.822 mmol) was added under argon.The reaction mixture was stirred at 55° C. for 14 h. The reactionmixture was diluted with dichloromethane, washed with 2N NaOH and brine,dried with sodium sulfate, filtered by suction and evaporated todryness; yield: 163 mg (68%).

56.6(R)-1-{4-[3-(4-Chloro-phenyl)-[1,2,4]triazol-4-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one

The acylation reaction was performed as described for example “A54”(step 54.6). Purification by flash chromatography (Companion RF, 12 gSi50 silica gel column DCM/MeOH (5%)); yield: 107 mg (43%); (purity:100%, Rt: 1.84 min, (M+H) 403.1-405.1); ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 8.66 (s, 1H), 7.71-7.49 (m, 4H), 6.66 (s, 1H), 4.71-4.54 (m, 2H),4.43-4.24 (m, 1H), 2.89-2.63 (m, 2H), 2.11-1.96 (m, 2H), 1.96-1.78 (m,2H), 1.58 (s, 3H).

(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[3-(4-methoxy-phenyl)-3H-[1,2,3]triazol-4-yl]-piperidin-1-yl}-2-methyl-propan-1-one(“A57”) 57.14-[3-(4-Methoxy-phenyl)-3H-[1,2,3]triazol-4-yl]-piperidine-1-carboxylicacid tert-butyl ester

4-Ethynyl-piperidine-1-carboxylic acid tert-butyl ester (300.0 mg; 1.167mmol) and 4-azidoanisole (191.4 mg; 1.284 mmol) were dissolved indioxane (4.0 mL). L-Ascorbic acid sodium salt (34.7 mg; 0.175 mmol) wasdissolved in water (0.2 mL) and added to the yellow solution whilestirring. The reaction solution was purged with argon and copper sulfatepentahydrate (6.2 mg; 0.023 mmol) was added in one portion. Thesuspension was purged with argon for 10 minutes and stirred 100° C. for7 h. The suspension was filtrated and the residue was washed withdioxane. The filtrate was evaporated to dryness. The oily residue wastriturated with diethyl ether, the precipitate was filtered off and thefiltrate was evaporated to dryness. The residue was used without furtherpurification; yield: 285 mg (64%) yellow oil.

57.2 4-[3-(4-Methoxy-phenyl)-3H-[1,2,3]triazol-4-yl]-piperidinehydrochloride

4-[3-(4-Methoxy-phenyl)-3H-[1,2,3]triazol-4-yl]-piperidine-1-carboxylicacid tert-butyl ester (269.0 mg; 0.750 mmol) was dissolved in HClsolution (4.0 M in dioxane; 4.0 mL) and stirred at room temperature for2.5 h. The reaction mixture was evaporated to dryness and the oilyresidue used without further purification; yield: 214 mg (97%).

57.3(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[3-(4-methoxy-phenyl)-3H-[1,2,3]triazol-4-yl]-piperidin-1-yl}-2-methyl-propan-1-one(“A57”)

4-[3-(4-Methoxy-phenyl)-3H-[1,2,3]triazol-4-yl]-piperidine hydrochloride(214.0 mg; 0.726 mmol) and(R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (229.5 mg; 1.452mmol) were dissolved in DMF (2.5 mL). The yellow solution was cooleddown with a water-ice-bath. N-Ethyldiisopropylamine (657 mg; 5.082 mmol)was added and HATU (607 mg; 1.597 mmol) was added in one portion,cooling was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and saturated sodiumcarbonate solution and extracted with ethyl acetate. The combinedorganic layers were washed with water and brine, dried over sodiumsulfate, filtrated and evaporated to dryness. The oily residue waspurified by RP-chromatography; yield: 95 mg (33%) colorless solid;(purity: 100%, Rt: 2.01 min, (M+H) 399.1); ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 8.51 (s, 1H), 7.77 (d, J=9.1 Hz, 2H), 7.12 (d, J=9.1 Hz, 2H), 7.04(s, 1H), 5.05-4.12 (m, 2H), 3.83 (s, 3H), 3.26-3.16 (m, 1H), 3.15-3.00(m, 1H), 2.99-2.73 (m, 1H), 2.17-1.86 (m, 2H), 1.81-1.39 (m, 5H).

(R)-1-{4-[3-(4-Chloro-phenyl)-3H-[1,2,3]triazol-4-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A58”)

Preparation according to the procedures described for example “A57”.Purification by preparative HPLC (Agilent®, Column: SunFire™ Prep C18OBD™ 5 μM; 30×150 mm). Pure fractions were lyophilized; yield: 39 mg(29%) off-white solid; (purity: 100%, Rt: 2.18 min, (M+H) 403.1-405.1);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 8.51 (s, 1H), 7.91-7.84 (m, 2H),7.65-7.57 (m, 2H), 6.72 (s, 1H), 4.58-4.46 (m, 2H), 3.18-3.04 (m, 3H),2.10-2.00 (m, 2H), 1.74-1.62 (m, 2H), 1.59-1.54 (m, 3H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(3-p-tolyl-3H-[1,2,3]triazol-4-yl)piperidin-1-yl]-propan-1-one (“A59”)

Preparation according to the procedures described for example “A57”.

Purification by preparative HPLC (Agilent®, Column: SunFire™ Prep C18OBD™ 5 μM; 30×150 mm). Pure fractions were lyophilized; yield: 15 mg(22%) off-white solid; (purity: 100%, Rt: 2.11 min, (M+H) 383.2);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 8.40 (s, 1H), 7.74-7.67 (m, 2H),7.39-7.31 (m, 2H), 6.70 (s, 1H), 4.57-4.47 (m, 2H), 3.17-3.03 (m, 3H),2.37 (s, 3H), 2.10-1.99 (m, 2H), 1.74-1.61 (m, 2H), 1.59-1.54 (m, 3H).

(R)-3,3,3-Trifluoro-1-{4-[3-(2-fluoro-4-methyl-phenyl)-3H-[1,2,3triazol-4-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A60”) 60.1 1-Azido-2-fluoro-4-methyl-benzene

To a mixture of of 2-fluoro-4-methyl-phenylamine (300.0 mg; 2.397 mmol)in glacial acetic acid (2.1 mL) and conc. H₂SO₄ (1 mL) was added sodiumnitrite (172 mg, 2.487 mmol) in water (1.5 mL) dropwise under vigorousstirring at 0-5° C. After 10 min aqueous urea was added to the reactionmixture to remove excess sodium nitrite. Then sodium azide (171 mg,2.637 mmol) in water (1.5 mL) was added to the reaction mixture at 0-5°C. for 3 h. The reaction mixture was stirred at room temperature for 14h, poured into ice water and the resulting mixture was rendered basicwith sodium hydroxide and extracted with ethyl acetate. The combinedorganic phases were washed with water, dried over sodium sulfate andconcentrated to give corresponding the azide, which was used in the nextstep without purification; yield: 150 mg (39%) brown oil; Rt: 2.50.

The following steps (60.2-60.3) were performed as described for example“A57”.

60.4(R)-3,3,3-Trifluoro-1-{4-[3-(2-fluoro-4-methyl-phenyl)-3H-[1,2,3]triazol-4-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A60”)

Preparation according to the procedures described for example “A57”.

Purification by preparative HPLC (Agilent®, Column: SunFire™ Prep C18OBD™ 5 μM; 30×150 mm). Pure fractions were lyophilized; yield: 17 mg(26%) beige solid; (purity: 99%, Rt: 2.13 min, (M+H) 401.2);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 8.22 (d, J=1.9 Hz, 1H), 7.65 (t, J=8.1Hz, 1H), 7.35-7.30 (m, 1H), 7.25-7.20 (m, 1H), 6.74 (s, 1H), 4.62-4.49(m, 2H), 3.19-3.05 (m, 3H), 2.43 (s, 3H), 2.11-2.01 (m, 2H), 1.76-1.63(m, 2H), 1.59-1.57 (m, 3H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(2-phenyl-imidazol-1-yl)-piperidin-1-yl]-propan-1-one(“A61”) 61.1 4-(2-Phenyl-imidazol-1-yl)-piperidine-1-carboxylic acidtert-butyl ester

4-Imidazol-1-yl-piperidine-1-carboxylic acid tert-butyl ester (100.0 mg;0.398 mmol), iodobenzene (105.5 mg; 0.517 mmol), palladium acetate (47%Pd; 2.7 mg; 0.012 mmol) and copper iodide (159.1 mg; 0.836 mmol) weresuspended in DMF (2.0 mL). The vial was sealed with a septum, argon wasbubbled through the reaction mixture for 5 min and the mixture wasstirred for 4 h at 140° C. in a microwave apparatus. The reactionmixture was diluted with ethyl acetate, washed with aqueous ammonia(15%), with water and brine, dried with sodium sulfate, filtered andevaporated to dryness. The residue was purified by flash chromatography(Companion RF; 24 g Si50 silica gel column; DCM/MeOH (2.5%)); yield: 153mg (43%); (Rt: 1.51 min, (M+H) 328.2).

61.2 4-(2-Phenyl-imidazol-1-yl)-piperidine tritrifluoroacetate

4-(2-Phenyl-imidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester(143.0 mg; 0.437 mmol) was dissolved in dichloromethane (1.0 mL).Trifluoroacetic acid (0.842 ml; 10.935 mmol) was added and the reactionmixture was stirred for 15 min at room temperature. The reaction mixturewas evaporated to dryness and the residue (249 mg) used in the next stepwithout further purification.

61.3(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(2-phenyl-imidazol-1-yl)piperidin-1-yl]-propan-1-one(“A61”)

4-(2-Phenyl-imidazol-1-yl)-piperidine tritrifluoroacetate (249.0 mg;0.437 mmol), (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid(138.2 mg; 0.875 mmol) and HATU (332.6 mg; 0.875 mmol) were dissolved inDMF (2.5 mL). NEthyldiisopropylamine (565.2 mg; 4.373 mmol) was addedand the reaction mixture was stirred at room temperature for 1.5 h. Thereaction mixture was diluted with water and extracted with ethylacetate. The combined organic layers were washed with saturated NaHCO₃solution and brine, dried with sodium sulfate, filtered and evaporatedto dryness. The residue was purified by flash chromatography (CompanionRF, 24 g Si50 silica gel column). The obtained product was suspended inacetonitrile (1.5 mL), filtered by suction, washed with littleacetonitrile and diethyl ether and dried under vacuum at 50° C. for 2 h.Yield: 92.5 mg (57%) colorless solid; (purity: 100%; Rt: 1.30 min, (M+H)368.2); ¹H NMR (400 MHz, DMSO-ds) δ [ppm] 7.59-7.40 (m, 6H), 7.15 (s,1H), 7.05 (d, J=1.3 Hz, 1H), 4.89-4.30 (m, 3H), 3.14-2.93 (m, 1H),2.75-2.55 (m, 1H), 2.05-1.73 (m, 4H), 1.54 (s, 3H).

(R)-1-{4-[2-(4-Chloro-phenyl)-imidazol-1-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A62”)

Preparation according to the procedures described for example “A61”.

Purification by flash chromatography (Companion RF, 24 g Si50 silica gelcolumn; DCM/MeOH (2.5%)); yield: 55 mg (68%) colorless solid; (purity:100%; Rt: 1.46 min, (M+H) 402.1-404.1); ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 7.60-7.54 (m, 2H), 7.54-7.48 (m, 2H), 7.37-7.33 (m, 1H), 7.03-6.99(m, 1H), 6.76 (s, 1H), 4.72-4.58 (m, 2H), 4.42-4.30 (m, 1H), 2.93-2.80(m, 2H), 2.01-1.91 (m, 2H), 1.91-1.77 (m, 2H), 1.59-1.52 (m, 3H).

(2R)-3,3,3-trifluoro-2-hydroxy-2-methyl-1-[4-(5-phenylimidazol-1-yl)-1-piperidyl]propan-1-one(“A63”) 63.1 N-[(E)-2-Phenyl-1-(toluene-4-sulfonyl)-vinyl]-formamide

Potassium tert-butylate (948 mg; 8.451 mmol) was dissolved in dry THF(12.0 mL) under argon and cooled to −40° C. A solution of1-isocyanomethanesulfonyl-4-methyl-benzene (1.5 g; 7.683 mmol) in dryTHF (6.0 mL) was added dropwise. The reaction mixture was stirred for 30min at −40° C. A solution of benzaldehyde (815 mg; 7.683 mmol) in dryTHF (6.0 mL) was added dropwise keeping the temperature at −40° C. Thereaction mixture was stirred at −40° C. for 20 min. The reaction mixturewas poured into ice water, neutralized with 1N HCl solution (pH=7) andextracted with dichloromethane. The combined organic layers were washedwith brine, dried with sodium sulfate, filtered by suction andevaporated to dryness. The solid residue was triturated withmethyl-tert-butyl ether, filtered by suction and washed with littlemethyl-tert-butyl ether and diethyl ether and dried. Yield: 2.0 g (86%),light brown solid (purity: 100%; Rt: 2.04 min, (M+H) 302.1).

63.2 4-(5-Phenyl-imidazol-1-yl)-piperidine-1-carboxylic acid ethyl ester

N-[(E)-2-Phenyl-1-(toluene-4-sulfonyl)-vinyl]-formamide (2.0 g; 6.637mmol) was dissolved in dry THF (30.0 mL) and cooled down to −10° C.Triethylamine (9.2 ml; 66.366 mmol) was added and the solution wasstirred for 10 min. Phosphoryl chloride (1.83 mL; 19.910 mmol) was addeddropwise over a period of 10 min keeping the temperature at −10° C. Thereaction mixture was stirred at −10° C. for additional 30 min. Thereaction mixture was poured into ice water and extracted withdichloromethane. The combined organic layers were washed with brine,dried with sodium sulfate, filtered by suction and evaporated todryness. The residue was dissolved in dry THF (25.0 mL) and addeddropwise to a solution of 4-amino-piperidine-1-carboxylic acid ethylester (2.29 g; 13.273 mmol) in methanol (15.0 mL) at room temperature.The reaction mixture was stirred at room temperature for 16 h. Thereaction mixture was evaporated to dryness. The oily residue wasdissolved in dichloromethane, washed with water and brine, dried withsodium sulfate, filtered by suction and evaporated to dryness. Theresidue was purified by flash chromatography (Companion RF; 120 g Si50silica gel column); yield: 387 mg (19%) brown oil (purity: 98.3%; Rt:1.37 min, (M+H) 300.2).

63.3 4-(5-Phenyl-imidazol-1-yl)-piperidine

4-(5-Phenyl-imidazol-1-yl)-piperidine-1-carboxylic acid ethyl ester(387.0 mg; 1.294 mmol) was dissolved in dry THF (20.0 mL) and cooled to0° C.

Methyllithium (5% solution in diethylether) (2.03 mL; 3.234 mmol) wasadded dropwise under argon over a period of 15 min. The reaction mixturewas stirred at 0° C. for additional 30 min. The reaction mixture waspoured into ice water and extracted with dichloromethane. The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered by suction and evaporated to dryness. The residue was reactedfurther without purification; yield: 164 mg (56%).

63.4(2R)-3,3,3-trifluoro-2-hydroxy-2-methyl-1-[4-(5-phenylimidazol-1-yl)-1-piperidyl]propan-1-one(“A63”)

4-(5-Phenyl-imidazol-1-yl)-piperidine (164.0 mg; 0.721 mmol),(R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (228.1 mg; 1.443mmol) and HATU (548.7 mg; 1.443 mmol) were dissolved in DMF (2.5 mL).N-Ethyldiisopropylamine (0.613 mL; 3.607 mmol) was added and thereaction mixture was stirred at room temperature for 45 min. Thereaction mixture was diluted with water and extracted with ethylacetate. The combined organic layers were washed with saturated NaHCO₃solution and brine, dried over sodium sulfate, filtered and evaporatedto dryness. The residue was purified by flash chromatography (CompanionRF, 40 g Si50 silica gel column). The residue was triturated in littledichloromethane, filtered by suction, washed with diethyl ether anddried under vacuum at 50° C. for 2 h; yield: 60 mg (23%) colorlesssolid; (purity: 100%; Rt: 1.40 min, (M+H) 368.2); ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 7.85-7.80 (m, 1H), 7.52-7.45 (m, 2H), 7.45-7.38 (m,3H), 6.96-6.91 (m, 1H), 6.77 (s, 1H), 4.72-4.58 (m, 2H), 4.33-4.22 (m,1H), 2.91-2.78 (m, 2H), 2.06-1.94 (m, 2H), 1.94-1.80 (m, 2H), 1.60-1.53(m, 3H).

(2R)-1-[4-[5-(4-chlorophenyl)imidazol-1-yl]-1-piperidyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A64”)

Preparation according to the procedures described for example “A63”.

Purification by flash chromatography (Companion RF, 12 g Si50 silica gelcolumn); yield: 104 mg (74%) colorless solid; (purity: 100%; Rt: 1.56min; (M+H) 402.1-404.1);

¹H NMR (400 MHz, DMSO-d₆) [ppm] 7.94 (s, 1H), 7.58-7.51 (m, 2H),7.49-7.41 (m, 2H), 7.08 (s, 1H), 6.98 (s, 1H), 4.90-4.36 (m, 2H),4.29-4.16 (m, 1H), 3.15-2.89 (m, 1H), 2.78-2.54 (m, 1H), 2.06-1.74 (m,4H), 1.54 (s, 3H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(3-phenyl-3H-imidazol-4-yl)piperidin-1-yl]-propan-1-one(“A65”) 65.11-[2-(1-tert-Butoxycarbonyl-piperidin-4-yl)-2-oxo-ethyl]-3,5,7-triaza-1-azonia-tricyclo[3.3.1.13,7]decanebromide

4-(2-Bromo-acetyl)-piperidine-1-carboxylic acid tert-butyl ester (500.0mg; 1.633 mmol) dissolved in chloroform (3.0 mL). Hexamethylenetetramine(0.172 ml; 1.633 mmol) was added and the solution was stirred at 50° C.for 1 h. The reaction mixture was cooled to 0° C. and the resultingprecipitate was filtered by suction and washed with littledichloromethane. The filtrate was evaporated to dryness. The residue wassuspended in diethyl ether, filtered by suction, washed with diethylether and dried under vacuum; yield: 725 mg (99%).

65.2 4-(2-Amino-acetyl)-piperidine-1-carboxylic acid tert-butyl estertosylate

1-[2-(1-tert-Butoxycarbonyl-piperidin-4-yl)-2-oxo-ethyl]-3,5,7-triaza-1-azonia-tricyclo[3.3.1.13,7]decanebromide (725.0 mg; 1.625 mmol) was dissolved in ethanol (3.0 mL) andtoluene-4-sulfonic acid hydrate (340.0 mg; 1,788 mmol) was added. Thereaction mixture was stirred at room temperature for 14 h. The reactionmixture was filtered by suction, washed with little ethanol and diethylether and dried under vacuum at 50° C. for 2 h; yield: 260 mg (39%).

65.3 4-[2-(3-Phenyl-thioureido)-acetyl]-piperidine-1-carboxylic acidtert-butyl ester

4-(2-Amino-acetyl)-piperidine-1-carboxylic acid tert-butyl estertosylate (121.0 mg; 0.292 mmol) was suspended in dry THF (5.0 mL) andphenyl isothiocyanate (78.3 mg; 0.579 mmol) was added. Triethylamine(107.4 mg; 1.061 mmol) was added and the reaction mixture was stirred atroom temperature for 1.5 h and at 55° C. for 1 h. The reaction mixturewas cooled to room temperature, diluted with dichloromethane, washedwith water and brine, dried with Na₂SO₄, filtered by suction andevaporated to dryness. The residue was by flash chromatography(Companion RF; 24 g Si50 silica gel column); yield: 45 mg (41%).

65.4 4-(3-Phenyl-3H-imidazol-4-yl)-piperidine tritrifluoroacetate

4-[2-(3-Phenyl-thioureido)-acetyl]-piperidine-1-carboxylic acidtert-butyl ester (180.0 mg; 0.477 mmol) was dissolved in glacial aceticacid (2.0 mL) and refluxed for 2 h. The reaction mixture was cooled to0-5° C. and hydrogen peroxide (30%; 0.488 ml; 4.773 mmol) was addeddropwise. The cooling bath was removed and the reaction mixture wasstirred for 5 min at 5° C. to room temperature. The reaction mixture wasdiluted with toluene and evaporated to dryness. The residue wasdissolved in dichloromethane (2.0 mL) and trifluoroacetic acid (0.368mL; 4.773 mmol) was added. The solution was stirred for 20 min at roomtemperature and evaporated to dryness. The residue was used in the nextstep without further purification.

65.5(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(3-phenyl-3H-imidazol-4-yl)-piperidin-1-yl]-propan-1-one(“A65”)

The acylation reaction was performed as described for example 61 (step61.3). Purification by flash chromatography (Companion RF, 24 g Si50silica gel column). The oily residue was crystallized by triturationwith acetonitrile. The crystals were filtered by suction, washed withlittle acetonitrile and diethyl ether and dried under vacuum at 60° C.for 2 h; yield: 63 mg (26%); (purity: 99.3%, Rt: 1.32 min, (M+H) 368.2);¹H NMR (400 MHz, DMSO-d₆) δ [ppm]7.63-7.47 (m, 4H), 7.44-7.36 (m, 2H),6.85 (s, 1H), 6.74 (s, 1H), 4.54-4.40 (m, 2H), 2.89-2.69 (m, 3H),1.80-1.68 (m, 2H), 1.55-1.38 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(5-phenyl-pyrazol-1-yl)-piperidin-1-yl]-propan-1-one(“A66”) 66.1 4-Pyrazol-1-yl-pyridine hydrochloride

4-Chloropyridinium chloride (500.0 mg; 3.333 mmol) and pyrazole (680.8mg; 9.999 mmol) were dissolved in acetonitrile (5.0 mL) and refluxed for14 h. The reaction solution was cooled down to ambient temperature, theformed precipitate was filtered by suction, washed with acetonitrile anddiethyl ether and dried under vacuum at room temperature for 2 h; yield:564 mg (93%).

66.2 4-Pyrazol-1-yl-piperidine hydrochloride

4-Pyrazol-1-yl-pyridine hydrochloride (564.0 mg; 3.105 mmol) wasdissolved in water (5.0 mL) and the mixture was hydrogenated with Rh—C(5%) at 8.3 bar and 65° C. for 14 h. The reaction solution was frozen inan acetone/dry ice bath and lyophilized for 14 h; yield: 528.5 mg (91%).

66.3 4-Pyrazol-1-yl-piperidine-1-carboxylic acid tert-butyl ester

4-Pyrazol-1-yl-piperidine hydrochloride (528.5 mg; 2.816 mmol) wasdissolved in THF (10.0 mL) and water (5.0 mL). Triethylamine (0.976 ml;7.039 mmol) was added followed by the addition of a solution ofdi-tert-butyl dicarbonate (0.663 ml; 3.097 mmol) in THF (5.0 mL).4-(Dimethylamino)pyridine (34.4 mg; 0.282 mmol) was added and thesolution was stirred at room temperature for 1.5 h. The reaction mixturewas diluted with dichloromethane, washed with water and brine, driedover sodium sulfate, filtered by suction and evaporated to dryness. Theresidue was purified by RP-chromatography (Companion RF; 86 g C18 silicagel column). Yield: 292 mg (41%); (purity: 100%, Rt: 2.01 min,(M+H-t-butyl) 196.1).

66.4 4-(5-Phenyl-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butylester

4-Pyrazol-1-yl-piperidine-1-carboxylic acid tert-butyl ester (292.0 mg;1.162 mmol), iodobenzene (355.5 mg; 1.743 mmol), tetrabutylammoniumacetate (700.6 mg; 2.324 mmol) and palladium acetate (36.3 mg; 0.162mmol) were dissolved in DMA (5.0 mL). The vial was sealed with a septum,argon was bubbled through the solution for 5 min and the solution wasstirred at 70° C. for 2 days. Palladium acetate (36.3 mg; 0.162 mmol)was added and reaction mixture was stirred at 75° C. for 66 h. Thereaction mixture was diluted with water and extracted with ethylacetate. The combined organic layers were washed with saturated NaHCO₃solution and brine, dried over sodium sulfate, filtered by suction andevaporated to dryness. The residue was purified by flash chromatography(Companion RF; SuperFlash SF25; 55 g C18 column). Yield: 107.5 mg (28%);(purity: 98.4%, 2.52 min, (M+H-t-butyl) 272.2).

66.5 4-(5-Phenyl-pyrazol-1-yl)-piperidine ditrifluoroacetate

4-(5-Phenyl-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester(107.5 mg; 0.328 mmol) was dissolved in dichloromethane (1.0 mL).Trifluoroacetic acid (0.631 ml; 8.189 mmol) was added and the reactionmixture was stirred at room temperature for 15 min. The reaction mixturewas evaporated to dryness; yield: 149 mg (100%); (HPLC: 99.2%, Rt: 1.32min; (M+H) 228.2).

66.6(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(5-phenyl-pyrazol-1-yl)piperidin-1-yl]-propan-1-one(“A66”)

The acylation reaction was performed as described for example “A62”(step 62.4). Purification by preparative HPLC (Agilent®, Column:SunFire™ Prep C18 OBD™ 5 μM; 30×150 mm); yield: 73 mg (61%); (purity:100%, Rt: 2.17 min, (M+H) 368.2); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]7.54-7.40 (m, 6H), 6.84 (s, 1H), 6.28 (d, J=1.8 Hz, 1H), 4.68-4.53 (m,2H), 4.46-4.35 (m, 1H), 2.98-2.83 (m, 2H), 2.13-1.98 (m, 2H), 1.94-1.82(m, 2H), 1.59-1.51 (m, 3H).

(R)-3,3,3-Trifluoro-1-{4-[1-(4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A67”) 67.1 4-(1H-Imidazol-2-yl)-piperidine-1-carboxylic acidtert-butyl ester

4-Formylpiperidine-1-carboxylic acid tert-butyl ester (3.23 g; 15.145mmol) was dissolved in methanol (6.74 ml; 11,000 aq.). Ammoniumhydroxide solution (32%; 17.40 mL) and 5 min later glyoxal (30% inwater; 2.57 mL; 15.902 mol) was added and the solution was stirred atroom temperature for 14 h. The reaction was diluted with brine and waterand extracted with dichloromethane. The combined organic layers weredried over sodium sulfate and evaporated to dryness. The oily residuewas purified by flash chromatography (CombiFlashRF 200); yield: 1.73 g(45%).

67.2 4-[1-(4-Fluoro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

4-(1H-Imidazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester(251.3 mg; 1.000 mmol), 4-fluorophenylboronic acid (285.6 mg; 2.000mmol), anhydrous copper acetate (286.8 mg; 1.500 mmol) and a littleamount of molecular sieves 4 Å was suspended in dry dichloromethane (6.0mL). Dry pyridine (0.163 ml; 2.000 mmol) was added and the reaction wasstirred at ambient temperature for 2 days. The reaction mixture wasevaporated to dryness and the residue purified by flash chromatography(CombiFlashRF 200); yield: 166 mg (43%); Rt: 1.7 min, (M+H) 346.2.

67.3 4-[1-(4-Fluoro-phenyl)-1H-imidazol-2-yl]-piperidine

Hydrogen chloride solution (4.0 M in dioxane; 3.0 mL) was added to4-[1-(4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acidtert-butyl ester (144.0 mg; 0.417 mmol) dissolved in dioxane (3.0 mL)and the mixture was stirred at ambient temperature for 14 h. Thereaction mixture was diluted with water and saturated aqueousNaHCO₃-solution (pH 8) and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated in vacuo; yield: 62 mg (61%).

67.4(R)-3,3,3-Trifluoro-1-{4-[1-(4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A67”)

4-[1-(4-Fluoro-phenyl)-1H-imidazol-2-yl]-piperidine (62.0 mg; 0.253mmol), (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid (40.0 mg;0.253 mmol) and HATU (105.7 mg; 0.278 mmol) were dissolved in DMF (10.0mL). N-Ethyldiisopropylamine (0.218 mL; 1.264 mmol) was added and thesolution was stirred at room temperature for 14 h. The mixture wasevaporated to dryness and the residue was purified by flashchromatography (CombiFlashRF 200); yield: 46 mg (47%); (purity: 100%),Rt: 1.41 min, (M+H) 386.2); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.52-7.46(m, 2H), 7.43-7.35 (m, 2H), 7.20 (d, J=1.3 Hz, 1H), 7.04 (s, 1H), 6.95(d, J=1.3 Hz, 1H), 4.77-4.20 (m, 2H), 3.14-2.80 (m, 2H), 2.76-2.53 (m,1H), 1.86-1.54 (m, 4H), 1.50 (s, 3H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(1-p-tolyl-1H-imidazol-2-yl)piperidin-1-yl]-propan-1-one(“A68”)

Preparation according to the procedures described for example “A67”.

Yield: 128 mg (53%); (purity: 100%, Rt: 1.47 min, (M+H) 382.2);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.38-7.32 (m, 2H), 7.32-7.27 (m, 2H),7.17 (d, J=1.4 Hz, 1H), 7.03 (s, 1H), 6.95 (d, J=1.3 Hz, 1H), 4.79-4.18(m, 2H), 3.12-2.82 (m, 2H), 2.72-2.53 (m, 1H), 2.39 (s, 3H), 1.84-1.55(m, 4H), 1.51 (s, 3H).

(R)-1-{4-[1-(4-Chloro-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A69”)

Preparation according to the procedures described for example “A67”.

Yield: 23 mg (22%); (purity: 100%, Rt: 1.52 min, (M+H) 402.1-404.1);

¹H NMR (400 MHz, DMSO-de) δ [ppm] 7.65-7.59 (m, 2H), 7.51-7.44 (m, 2H),7.23 (d, J=1.4 Hz, 1H), 7.03 (s, 1H), 6.96 (d, J=1.3 Hz, 1H), 4.77-4.22(m, 2H), 3.16-2.81 (m, 2H), 2.78-2.53 (m, 1H), 1.86-1.54 (m, 4H), 1.51(s, 3H).

(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[1-(4-methoxy-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-2-methyl-propan-1-one(“A70”)

Preparation according to the procedures described for example “A67”.

Yield: 90 mg (42%); (purity: 100%, Rt: 1.44 min, (M+H) 398.3);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.42-7.34 (m, 2H), 7.28 (s, 1H),7.16-7.06 (m, 3H), 7.03 (s, 1H), 4.81-4.21 (m, 2H), 3.83 (s, 3H),3.09-2.84 (m, 2H), 2.75-2.54 (m, 1H), 1.85-1.56 (m, 4H), 1.51 (s, 3H).

(R)-3,3,3-Trifluoro-1-{4-[4-(4-fluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A71”) 71.1 4-[1,3,4]Oxadiazol-2-yl-piperidine-1-carboxylic acidtert-butyl ester

4-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (1.40g; 5.754 mmol) was suspended in trimethyl orthoformate (10.0 mL),toluene-4-sulfonic acid monohydrate (109.5 mg; 0.575 mmol) was added andthe mixture was refluxed at 130° C. for 4 h. The reaction mixture wasdiluted with water and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated in vacuo. The residue was purified by flashchromatography (CombiFlashRF 200).

Yield: 1.04 g (71%); Rt: 1.78 min, (M+H-t-butyl) 198.1.

71.24-[4-(4-Fluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-piperidine-1-carboxylicacid tert-butyl ester

A mixture of 4-[1,3,4]oxadiazol-2-yl-piperidine-1-carboxylic acidtert-butyl ester (188.0 mg; 0.742 mmol) and trifluoroacetic acid (0.058mL; 0.742 mmol) were dissolved toluene (3.0 mL). 4-fluoraniline (165.0mg; 1.484 mmol) was added and the mixture was stirred at 110° C. for 14h. The mixture was concentrated in vacuo and the residue purified byRP-flash chromatography (CombiFlashRF 200); yield: 151 mg (59%)colorless oil; (purity 98%, Rt: 2.03 min, (M+H) 347.2).

71.3 4-[4-(4-Fluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-piperidinehydrochloride

BOC-deprotection was performed as described for example “A32” (step32.3). The isolated product was used in the next step without furtherpurification.

71.4(R)-3,3,3-Trifluoro-1-{4-[4-(4-fluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A71”)

The acylation reaction was performed as described for example “A27”.

Yield: 74 mg (42%); (purity: 100%, Rt: 1.75 min, (M+H) 387.2);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 8.61 (s, 1H), 7.65-7.55 (m, 2H),7.49-7.39 (m, 2H), 7.06 (s, 1H), 4.79-4.16 (m, 2H), 3.15-2.89 (m, 2H),2.84-2.57 (m, 1H), 1.88-1.57 (m, 4H), 1.51 (s, 3H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(4-phenyl-4H-[1,2,4]triazol-3-yl)piperidin-1-yl]-propan-1-one(“A72”)

Preparation according to the procedures described for example “A71”.

Yield: 55 mg (50%); (purity: 100%, Rt: 1.70 min, (M+H) 369.1);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 8.63 (s, 1H), 7.65-7.49 (m, 5H), 7.07(s, 1H), 4.82-4.16 (m, 2H), 3.17-2.92 (m, 2H), 2.82-2.56 (m, 1H),1.89-1.57 (m, 4H), 1.50 (s, 3H).

(R)-1-{4-[4-(4-Chloro-phenyl)-4H-[1,2,4]triazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A73”)

Preparation according to the procedures described for example “A71”.

Yield: 165 mg (67%); (purity: 100%, Rt: 1.89 min, (M+H) 403.1-405.1);

¹H NMR (400 MHz, DMSO-d₆) 5 [ppm] 9.19 (s, 1H), 7.77-7.63 (m, 4H),7.47-6.73 (m, 1H), 4.80-4.17 (m, 2H), 3.18-2.98 (m, 2H), 2.81-2.59 (m,1H), 1.90-1.60 (m, 4H), 1.51 (s, 3H).

The following compounds have been prepared analogously:

(R)-1-[4-(2-Cyclopropyl-2H-pyrazol-3-yl)-1-piperidyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A74”)

Purification by prep. HPLC; yield: 65 mg (9%) off-white solid; (purity98.9%, Rt: 2.87 min, (M+H) 332.0); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]7.23 (d, J=1.4 Hz, 1H), 7.08 (s, 1H), 6.04 (s, 1H), 4.81-4.79 (m, 1H),4.47-4.45 (m, 1H), 3.61-3.56 (m, 1H), 3.20-3.17 (m, 2H), 2.72-2.69 (m,1H), 1.96-1.94 (m, 2H), 1.55-1.40 (m, 5H), 1.22-1.03 (m, 2H), 0.99-0.95(m, 2H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[2-(1-methyl-piperidin-4-yl)-2H-pyrazol-3-yl]-piperidin-1-yl}-propan-1-one(“A75”)

Purification by prep. HPLC; yield: 5 mg (1%) off-white solid; (purity97.7%, Rt: 2.51 min, (M+H) 389.2); ¹H (400 MHz, MeOH-d₄) δ [ppm] 7.40(d, J=1.9 Hz, 1H), 6.09 (d, J=1.9 Hz, 1H), 4.89-4.88 (m, 1H), 4.62-4.60(m, 1H), 4.25-4.23 (m, 1H), 3.15-3.13 (m, 3H), 3.10-3.03 (m, 2H),2.36-2.27 (m, 7H), 1.96-1.86 (m, 2H), 1.63-1.62 (m, 2H), 1.50-1.41 (m,5H).

(R)-3,3,3-Trifluoro-2-hydroxy-1-[4-(2-isobutyl-1H-pyrazol-3-yl)-1-piperidyl]-2-methyl-propan-1-one(“A76”)

76.1 (4-(2H-Pyrazol-3-yl)-piperidine-1-carboxylic acid tert-butyl esterA stirred solution of4-((E)-3-dimethylamino-acryloyl)-piperidine-1-carboxylic acid tert-butylester (2.00 g; 7.02 mmol) and hydrazine monohydrate (0.69 mL; 14.04mmol) in ethanol (20.00 mL) was heated at 80° C. for 3 h. The reactionmixture was concentrated and the residue was diluted withdichloromethane (50 mL) and washed with water (30 mL). The aqueous layerwas back extracted with dichloromethane (2×15 mL). The combined organiclayers were washed with brine (10 mL), dried over Na₂SO₄ andconcentrated in vacuum to give4-(2H-pyrazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.60g; 6.22 mmol; 89%). The crude product was used for next step withoutfurther purification.

76.2 (4-(2-Isobutyl-2H-pyrazol-3-yl)-piperidine-1-carboxylic acidtert-butyl ester)/4-(1-Isobutyl-1H-pyrazol-3-yl)-piperidine-1-carboxylicacid tert-butyl ester

To a stirred solution of 4-(2H-pyrazol-3-yl)-piperidine-1-carboxylicacid tert-butyl ester (1.0 g; 3.887 mmol) in DMF (5.0 mL), potassiumcarbonate (1.7 g; 11.662 mmol) was added. 1-bromo-2-methyl-propane (1.08g; 7.775 mmol) was added gradually over a period of 15 min and thereaction mixture was stirred at 110° C. for 14 h. The reaction mixturewas cooled to room temperature, diluted with water and extracted withethyl acetate. The combined organic layers were dried over sodiumsulfate, filtered and concentrated in vacuum. The crude product waspurified by column chromatography. The obtained product (2.5 g; 16%) wasa mixture of two regioisomers, which were taken for next step withoutseparation.

76.34-(2-Isobutyl-2H-pyrazol-3-yl)-piperidine)/4-(1-isobutyl-1H-pyrazol-3-yl)-piperidine

Cleavage of the BOC-group was performed as described before resulting ina crude mixture of two regioisomers, which were taken for next stepwithout separation (300 mg; light yellow oil).

76.4(R)-3,3,3-Trifluoro-2-hydroxy-1-[4-(2-isobutyl-2H-pyrazol-3-yl)piperidin-1-yl]-2-methyl-propan-1-one

Preparation as described above; the crude residue was purified bypreparative HPLC; yield: 10 mg (4%) brown gum); (purity 95.8%, Rt: 3.76min, (M+H) 348.3); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 7.54 (d, J=2.0 Hz,1H), 7.04 (s, 1H), 6.04 (s, 1H), 4.68-4.65 (m, 1H), 4.35-4.33 (m, 1H),3.81 (d, J=7.2 Hz, 2H), 3.16-3.14 (m, 1H), 2.83-2.75 (m, 2H), 2.08-2.01(m, 1H), 1.90-1.88 (m, 2H), 1.51-1.40 (m, 5H), 0.80 (d, J=6.68 Hz, 6H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[2-(2,2,2-trifluoro-ethyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-propan-1-one(“A77”)

Purification by prep. HPLC; yield: 40 mg (5%) colorless solid; (purity99.2%, Rt: 3.65 min, (M+H) 374.0); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]7.46 (d, J=1.8 Hz, 1H), 7.07 (s, 1H), 6.20 (s, 1H), 5.11 (q, J=9.04 Hz,2H), 4.83-4.81 (m, 1H), 4.48-4.46 (m, 1H), 3.10-3.08 (m, 2H), 2.79-2.76(m, 1H), 1.81-1.78 (m, 2H), 1.53-1.35 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-1-[4-[2-(2-methoxyethyl)-2H-pyrazol-3-yl]-1-piperidyl]-2-methyl-propan-1-one(“A78”)

Purification by prep. HPLC; yield: 105 mg (15%) colorless oil; (purity98.2%, Rt: 2.84 min, (M+H) 350.0); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]7.33 (d, J=1.7 Hz, 1H), 7.06 (s, 1H), 6.03 (s, 1H), 4.80-4.78 (m, 1H),4.47-4.45 (m, 1H), 4.20 (t, J=5.4 Hz, 2H), 3.65 (t, J=5.4 Hz, 2H), 3.18(s, 3H), 3.05-3.03 (m, 2H), 2.71-2.69 (m, 1H), 1.86-1.84 (m, 2H),1.52-1.30 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-piperidin-1-yl}-propan-1-one(“A79”)

Purification by prep. HPLC; yield: 18 mg (36%) pale brown solid; (purity97.5%, Rt: 2.51 min, (M+H) 383.0); ¹H NMR (400 MHz, DMSO-d6) δ[ppm] 8.56(s, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.62 (s, 1H), 7.44 (d, J=8.2 Hz, 1H),7.05 (s, 1H), 6.37 (s, 1H), 4.71-4.69 (m, 1H), 4.48-4.38 (m, 1H),2.98-2.88 (m, 3H), 2.56 (s, 3H), 1.82-1.79 (m, 2H), 1.50-1.45 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-[6-(trifluoromethyl)-3-pyridyl]-2H-pyrazol-3-yl]-1-piperidyl]propan-1-one(“A80”)

Purification by column chromatography and finally by trituration withhexane; yield: 165 mg (47%) colorless solid; (purity 97.2%, Rt: 4.24min, (M+H) 437.0); ¹H NMR (400 MHz, DMSO-d6) δ[ppm] 8.97 (d, J=2.0 Hz,1H), 8.28-8.26 (m, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H),7.06-7.05 (m, 1H), 6.48 (brs, 1H), 4.73-4.71 (m, 1H), 4.41-4.39 (m, 1H),3.12-3.04 (m, 2H), 2.68-2.63 (m, 1H), 1.88-1.85 (m, 2H), 1.52-1.40 (m,5H).

5-{5-[1-((R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-pyrazol-1-yl}-pyridine-2-carbonitrile(“A81”)

Yield: 13 mg (32%) off-white solid; (purity 94.6%, Rt: 3.58 min, (M+H)394.0); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 8.96-8.94 (m, 1H), 8.25 (d,J=1.1 Hz, 2H), 7.74 (d, J=1.72 Hz, 1H), 7.05 (s, 1H), 6.48 (brs, 1H),4.72-4.70 (m, 1H), 4.40-4.38 (m, 1H), 3.14-3.12 (m, 1H), 2.97-2.95 (m,1H), 2.71-2.50 (m, 1H), 1.85-1.82 (m, 2H), 1.50-1.40 (m, 5H).

(R)-1-[4-[2-(3,5-Difluoro-2-pyridyl)-2H-pyrazol-3-yl]-1-piperidyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A82”)

Purification by RP-flash chromatography (CombiFlashRF 200); yield: 66 mg(29%) colorless solid; (purity 100%, Rt: 1.93 min, (M+H) 405.1); ¹H NMR(500 MHz, DMSO-d₆) δ [ppm] 8.56 (d, J=2.5 Hz, 1H), 8.34-8.27 (m, 1H),7.66 (d, J=1.8 Hz, 1H), 7.02 (s, 1H), 6.39 (d, J=1.8 Hz, 1H), 4.88-4.26(m, 2H), 3.07-2.82 (m, 2H), 2.68-2.41 (m, 1H), 1.88-1.70 (m, 2H),1.65-1.37 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[2-(5-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-piperidin-1-yl}-propan-1-one(“A83”)

Purification by column chromatography and finally by trituration withhexane; yield: 20 mg (6%) colorless solid; (purity 99.6%, Rt: 3.92 min,(M+H) 383.0); ¹H NMR (400 MHz, MeOH-d₄) δ [ppm] 8.37 (s, 1H), 7.84-7.81(m, 1H), 7.62 (d, J=8.0 Hz, 2H), 6.36 (s, 1H), 5.11-5.09 (m, 1H),4.58-4.56 (m, 1H), 3.73-3.71 (m, 1H), 3.09-3.07 (m, 1H), 2.71-2.68 (m,1H), 2.42 (s, 3H), 2.06-2.03 (m, 2H), 1.70-1.50 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[2-(5-trifluoromethyl-pyridin-2-yl)-2H-pyrazol-3-yl]-piperidin-1-yl}-propan-1-one(“A84”)

Purification by basic alumina chromatography; yield: 110 mg (68%)off-white solid; (purity 99.1%, Rt: 4.95 min, (M+H) 437.3); ¹H NMR (400MHz, DMSO-d₆) δ [ppm] 8.92 (s, 1H), 8.39-8.36 (m, 1H), 8.07 (d, J=8.80Hz, 1H), 7.76 (d, J=1.20 Hz, 1H), 7.08 (s, 1H), 6.48 (s, 1H), 4.83-4.80(m, 1H), 4.50-4.49 (m, 1H), 3.91 (t, J=11.20 Hz, 1H), 3.32-3.31 (m, 1H),3.10-3.01 (m, 1H), 2.06-1.98 (m, 2H), 1.53-1.50 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(1-methylpyrazol-4-yl)-2H-pyrazol-3-yl]-1-piperidyl]propan-1-one(“A85”)

Purification by column chromatography; yield: 285 mg (48%) off-whitesolid; (purity 99.5%, Rt: 4.18 min, (M+H) 372.0); ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 8.08 (s, 1H), 7.68 (s, 1H), 7.50 (d, J=2.0 Hz, 1H),7.06 (s, 1H), 6.25 (br s, 1H), 4.75-4.73 (m, 1H), 4.39-4.35 (m, 1H),3.89 (s, 3H), 3.05-2.93 (m, 2H), 2.70-2.59 (m, 1H), 1.90-1.70 (m, 2H),1.60-1.35 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(4-methylthiazol-2-yl)-2H-pyrazol-3-yl]-1-piperidyl]propan-1-one(“A86”)

Purification by column chromatography; yield: 120 mg (31%) off-whitesolid; (purity 98.3%, Rt: 4.53 min, (M+H) 389.0); ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 7.69 (d, J=1.6 Hz, 1H), 7.08-7.07 (m, 2H), 6.43 (br s,1H), 4.83-4.81 (m, 1H), 4.50-4.48 (m, 1H), 3.88-3.82 (m, 1H), 3.08-3.06(m, 1H), 2.69-2.65 (m, 1H), 2.35 (s, 3H), 2.07-2.05 (m, 2H), 1.65-1.53(m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[2-(1H-imidazol-2-yl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-methyl-propan-1-one(“A87”)

(R)-3,3,3-Trifluoro-1-[4-[2-[2-fluoro-4-(trifluoromethyl)phenyl]-2H-pyrazol-3-yl]-1-piperidyl]-2-hydroxy-2-methyl-propan-1-one(“A88”)

Purification by column chromatography; yield: 130 mg (25%) colorlesssolid; (purity 97.2%, Rt: 4.66 min, (M+H) 454.0); ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 8.05 (d, J=9.7 Hz, 1H), 7.81-7.76 (m, 2H), 7.69 (s,1H), 7.05 (s, 1H), 6.41 (br s, 1H), 4.70-4.68 (m, 1H), 2.98-2.96 (m,1H), 2.75-2.73 (m, 1H); 2.49-2.47 (m, 1H), 1.75-1.73 (m, 2H), 1.50-1.35(m, 6H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-[2-(trifluoromethyl)phenyl]-2H-pyrazol-3-yl]-1-piperidyl]propan-1-one(“A89”)

Purification by column chromatography; yield: 400 mg (51%) brown gum;(purity 98.5%, Rt: 4.67 min, (M+H) 436.0); ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 7.91-7.90 (m, 2H), 7.81 (t, J=7.7 Hz, 1H), 7.68 (t, J=7.7 Hz, 1H),7.59 (d, J=7.9 Hz, 1H), 7.05 (s, 1H), 6.39 (d, J=2.4 Hz, 1H), 4.67-4.65(m, 1H), 4.33-4.31 (m, 1H), 3.20-3.18 (m, 1H), 2.97-2.95 (m, 1H),2.86-2.84 (m, 1H), 1.96-1.94 (m, 2H), 1.70-1.52 (m, 5H).

(R)-3,3,3-Trifluoro-1-{4-[2-(4-fluoro-2-methoxy-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A90”)

Yield: 77 mg (70%) pale yellow solid; (purity 97.5%, Rt: 3.89 min, (M+H)416.0); ¹H NMR (400 MHz, DMSO-d6) δ [ppm] 7.51 (d, J=1.72 Hz, 1H),7.37-7.33 (m, 1H), 7.19-7.15 (m, 1H), 7.06 (s, 1H), 6.93-6.88 (m, 1H),6.24 (brs, 1H), 4.69-4.67 (m, 1H), 4.36-4.34 (m, 1H), 3.77 (s, 3H),2.92-2.89 (m, 1H), 2.70-2.49 (m, 1H), 1.68-1.62 (m, 3H), 1.49-1.30 (m,5H).

3-Fluoro-4-[5-[1-[(R)-3,3,3-trifuoro-2-hydroxy-2-methyl-propanoyl]-4-piperidyl]-2H-pyrazol-1-yl]benzonitrile(“A91”)

Purification by column chromatography and finally by trituration withhexane; yield: 30 mg (8%) off-white solid; (purity 94.0%, Rt: 3.96 min,(M+H) 411.0); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 8.21 (dd, J=10.0, 1.6Hz, 1H), 7.91 (dd, J=8.0, 1.20 Hz 1H), 7.80 (t, J=8.0 Hz, 1H), 7.69 (d,J=2.0 Hz, 1H), 7.05 (s, 1H), 6.41 (brs, 1H), 4.70-4.67 (m, 1H),4.39-4.37 (m, 1H), 2.97-2.95 (m, 2H), 2.74-2.72 (m, 1H), 1.75-1.72 (m,2H, 1.50-1.37 (m, 5H).

(R)-3,3,3-Trifluoro-1-[4-[2-[2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]-2H-pyrazol-3-yl]-1-piperidyl]-2-hydroxy-2-methyl-propan-1-one(“A92”)

Purification by prep. HPLC; yield: 45 mg (16%) off-white solid; (purity94.8%, Rt: 3.67 min, (M+H) 444.2); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]7.60 (d, J=1.6 Hz, 1H), 7.52-7.47 (m, 1H), 7.45-7.42 (m, 2H), 7.04 (s,1H), 6.34 (brs, 1H), 5.31 (s, 1H), 4.72-4.70 (m, 1H), 4.39-4.37 (m, 1H),2.95-2.93 (m, 1H), 2.69-2.65 (m, 1H), 1.75-1.73 (m, 2H), 1.52-1.47 (m,12H).

(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[2-(6-methoxy-pyridazin-3-yl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-methyl-propan-1-one(“A93”)

(R)-3,3,3-Trifluoro-2-hydroxy-1-[4-[2-(4-hydroxycyclohexyl)-2H-pyrazol-3-yl]-1-piperidyl]-2-methyl-propan-1-one(“A94”)

Purification by RP-flash chromatography (CombiFlashRF 200); yield: 35 mg(73%) colorless solid; (purity 100%, Rt: 1.64 min, (M+H) 390.2); ¹H NMR(400 MHz, DMSO-d₆) δ [ppm] 7.30 (d, J=1.8 Hz, 1H), 7.06 (s, 1H), 5.99(d, J=1.8 Hz, 1H), 4.92-4.33 (m, 3H), 4.26-4.03 (m, 1H), 3.57-3.42 (m,1H), 3.23-2.63 (m, 3H), 2.03-1.66 (m, 9H), 1.63-1.19 (m, 6H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-[4-(trifluoromethoxy)-phenyl]-2H-pyrazol-3-yl]-1-piperidyl]propan-1-one(“A95”)

Purification by RP-flash chromatography (CombiFlashRF 200); yield: 104mg (67%) colorless solid; (purity 100%, Rt: 2.31 min, (M+H) 452.2); ¹HNMR (400 MHz, DMSO-d₆) δ [ppm] 7.67-7.60 (m, 3H), 7.55 (d, J=8.4 Hz,2H), 7.04 (s, 1H), 6.38 (s, 1H), 4.93-4.20 (m, 2H), 3.09-2.94 (m, 2H),2.70-2.54 (m, 1H), 1.89-1.74 (m, 2H), 1.61-1.47 (m, 5H).

(R)-1-[4-[2-[4-(Difluoromethoxy)phenyl]-2H-pyrazol-3-yl]-1-piperidyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A96”)

Purification by RP-flash chromatography (CombiFlashRF 200); yield: 139mg (69%) colorless solid; (purity 100%, Rt: 2.15 min, (M+H) 434.2); ¹HNMR (400 MHz, DMSO-d₆) δ [ppm] 7.57 (d, J=1.8 Hz, 1H), 7.56-7.14 (m,5H), 7.02 (s, 1H), 6.39-6.27 (m, 1H), 5.02-4.14 (m, 2H), 3.06-2.91 (m,2H), 2.64-2.53 (m, 1H), 1.86-1.72 (m, 2H), 1.68-1.37 (m, 5H).

(R)-1-{4-[2-(2,4-Difluoro-phenyl)-5-methyl-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A97”)

Purification by RP-flash chromatography (CombiFlashRF 200); yield: 126mg (76%) colorless solid; (purity 99.6%, Rt: 2.10 min, (M+H) 418.2); ¹HNMR (400 MHz, DMSO-d₆) δ [ppm] 7.64-7.50 (m, 2H), 7.30-7.22 (m, 1H),7.01 (s, 1H), 6.12 (s, 1H), 4.88-4.17 (m, 2H), 3.06-2.79 (m, 1H),2.67-2.52 (m, 2H), 2.17 (s, 3H), 1.79-1.63 (m, 2H), 1.61-1.32 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(5-methyl-2-phenyl-2H-pyrazol-3-yl)-piperidin-1-yl]-propan-1-one(“A98”)

Purification by RP-flash chromatography (CombiFlashRF 200); yield: 259mg (81%) colorless solid; (purity 99.5%, Rt: 2.04 min, (M+H) 382.2); ¹HNMR (400 MHz, DMSO-d₆) δ [ppm] 7.56-7.48 (m, 2H), 7.48-7.39 (m, 3H),7.02 (s, 1H), 6.12 (s, 1H), 4.83-4.27 (m, 2H), 3.01-2.87 (m, 2H),2.65-2.49 (m, 1H), 2.18 (s, 3H), 1.86-1.70 (m, 2H), 1.63-1.32 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(1-methyl-1H-pyrazol-3-yl)piperidin-1-yl]-propan-1-one(“A99”)

The synthesis of “A21” also provided a regioisomer, which was separatedby preparative HPLC; yield: 30 mg (4%) colorless oil; (purity 98.4%, Rt:2.59 min, (M+H) 306.0); ¹H (400 MHz, DMSO-d₆) δ [ppm] 7.53 (d, J=2.0 Hz,1H), 7.04 (s, 1H), 6.04 (d, J=2.0 Hz, 1H), 4.70-4.60 (m, 1H), 4.42-4.34(m, 1H), 3.75 (s, 3H), 3.11-3.09 (m, 1H), 2.84-2.72 (m, 2H), 1.90-1.87(m, 2H), 1.55-1.30 (m, 5H).

(R)-1-{4-[2-(4-Chloro-3-fluoro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A100”)

Purification by RP-flash chromatography (CombiFlashRF 200); yield: 91 mg(66%) colorless solid; (purity 98.3%, Rt: 2.27 min, (M+H) 420.1-422.1);¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 7.77 (t, J=8.4 Hz, 1H), 7.66 (dd,J=10.0, 2.4 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.47-7.35 (m, 1H), 7.03 (s,1H), 6.38 (s, 1H), 4.88-4.23 (m, 2H), 3.15-2.54 (m, 3H), 1.93-1.28 (m,7H).

(R)-1-{4-[2-(3,4-Dichloro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A101”)

Purification by RP-flash chromatography (CombiFlashRF 200); yield: 192mg (86%) colorless solid; (purity 100%, Rt: 2.37 min, (M+H)436.0-440.0);

¹H NMR (500 MHz, DMSO-d₆) 5 [ppm] 7.87-7.76 (m, 2H), 7.63 (d, J=1.8 Hz,1H), 7.54 (dd, J=8.6, 2.5 Hz, 1H), 7.03 (s, 1H), 6.38 (s, 1H), 4.92-4.21(m, 2H), 3.19-2.55 (m, 3H), 1.98-1.35 (m, 7H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[1-(5-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-3-yl]-piperidin-1-yl}-propan-1-one (“A102”)

Purification by prep. HPLC; yield: 175 mg (28%) off-white solid; (purity98.9%, Rt: 5.11 min, (M+H) 437.0); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]8.84 (dd, J=1.5, 0.8 Hz, 1H), 8.58 (d, J=2.7 Hz, 1H), 8.33 (dd, J=2.4,9.0 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.07 (s, 1H), 6.56 (d, J=2.6 Hz,1H), 4.74-4.72 (m, 1H), 4.39-4.37 (m, 1H), 3.20-3.19 (m, 1H), 3.02-2.99(m, 1H), 2.81-2.78 (m, 1H), 2.00-1.98 (m, 2H), 1.68-1.66 (m, 2H),1.53-1.52 (m, 3H).

(R)-1-{4-[1-(5-Chloro-pyrimidin-2-yl)-1H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A103”)

Purification by prep. HPLC; yield: 16 mg (15%) colorless solid; (purity100%, Rt: 2.01 min, (M+H) 404.0-406.0); ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 8.94 (s, 2H), 8.53 (d, J=2.7 Hz, 1H), 7.07 (s, 1H), 6.54 (d, J=2.7Hz, 1H), 4.89-4.31 (m, 2H), 3.29-3.08 (m, 1H), 3.07-2.94 (m, 1H),2.91-2.71 (m, 1H), 2.06-1.90 (m, 2H), 1.80-1.43 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(2H-pyrazol-3-yl)-piperidin-1-yl]-propan-1-one(“A104”)

Purification by prep. HPLC; yield: 11 mg (6%) colorless solid; (purity100%, Rt: 1.53 min, (M+H) 292.1); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]12.68-12.29 (m, 1H), 7.68-7.27 (m, 1H), 7.03 (s, 1H), 6.06 (s, 1H),4.84-4.28 (m, 2H), 3.24-3.04 (m, 1H), 2.99-2.65 (m, 2H), 2.00-1.84 (m,2H), 1.67-1.40 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[1-(6-methoxy-pyridazin-3-yl)-1H-pyrazol-3-yl]-piperidin-1-yl}-2-methyl-propan-1-one(“A105”)

Purification by RP-flash chromatography (CombiFlashRF 200); yield: 93 mg(51%) colorless solid; (purity 98.2%, Rt: 2.04 min, (M+H) 400.1); ¹H NMR(500 MHz, DMSO-d₆) δ [ppm] 8.63 (d, J=2.6 Hz, 1H), 8.15 (d, J=9.4 Hz,1H), 7.47 (d, J=9.4 Hz, 1H), 7.11 (s, 1H), 6.59 (d, J=2.6 Hz, 1H),5.05-4.25 (m, 2H), 4.11 (s, 3H), 3.34-2.67 (m, 3H), 2.11-1.95 (m, 2H),1.85-1.45 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[(3S,4S)-3-methyl-4-(2-phenyl-2H-pyrazol-3-yl)-piperidin-1-yl]-propan-1-one(“A106”)

Purification by RP-flash chromatography (CombiFlashRF 200); yield: 13 mg(28%) colorless solid; (purity 100%, Rt: 2.07 min, (M+H) 382.1); ¹H NMR(500 MHz, DMSO-d₆, 90° C.) δ [ppm] 7.59-7.36 (m, 6H), 6.68 (s, 1H), 6.26(d, J=1.6 Hz, 1H), 4.59-4.42 (m, 1H), 4.22-4.04 (m, 1H), 3.30-3.17 (m,1H), 3.17-3.05 (m, 1H), 2.94-2.82 (m, 1H), 1.99-1.81 (m, 1H), 1.78-1.61(m, 2H), 1.61-1.42 (m, 3H), 0.60 (d, J=7.0 Hz, 3H).

(R)-3,3,3-Trifluoro-1-{(3S,4S)-4-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A107”) and(R)-3,3,3-Trifluoro-1-{(3R,4R)-4-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A108”)

107.1/108.1(3S,4S)-4-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidine-1-carboxylicacid tert-butyl ester and(3R,4R)-4-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidine-1-carboxylicacid tert-butyl ester

4-Acetyl-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (250.0mg; 1.015 mmol) and tert-Butoxy bis(dimethylamino)methane (187.7 mg;1.066 mmol) were placed in a vial and stirred for 45 min at 100° C. Aclear, yellow solution was formed. The mixture was cooled to roomtemperature and diluted with ethanol (2.5 mL).(4-Fluoro-phenyl)-hydrazine hydrochloride (168.4 mg; 1.015 mmol) wasadded and the mixture was heated at 80° C. for 3 h. The mixture wasevaporated to dryness and the residue purified by RP-flashchromatography (CombiFlashRF 200). The pure fractions were combined,acetonitrile was removed in vacuo, diluted with saturated aqueousNaHCO3-solution and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over sodium sulfate, filtered andconcentrated in vacuo; yield: 215 mg (59%) orange-red oil (cis/trans:95/5).

210 mg of this diastereomeric mixture was separated by chiralchromatography:

SFC; Column: ChiralPak AD-H; eluent: CO₂/Methanol: 95/5; 220 nm

Yield: 108.1: 83 mg (40%), yellow oil;

-   -   107.1: 71 mg (34%), yellow oil.

107.2(3S,4S)-4-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidinehydrochloride

Preparation as described for example “A32” (step 32.3).

107.3(R)-3,3,3-Trifluoro-1-{(3S,4S)-4-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A107”)

Preparation and purification as described for example “A32” (step 32.4);yield: 33 mg (79%) colorless solid; (purity 100%, Rt: 2.1 min, (M+H)400.1); HPLC (Chiralpak AD-H; CO₂/MeOH-95/5): Rt 3.32 min; ¹H NMR (400MHz, DMSO-d₆, 90° C.) δ [ppm] 7.56 (d, J=1.7 Hz, 1H), 7.53-7.45 (m, 2H),7.38-7.29 (m, 2H), 6.74 (br. s, 1H), 6.27 (d, J=1.7 Hz, 1H), 4.63-4.44(m, 1H), 4.23-4.10 (m, 1H), 3.24-2.88 (m, 3H), 1.92 (qd, J=11.4, 4.2 Hz,1H), 1.78-1.66 (m, 2H), 1.62-1.51 (m, 3H), 0.62 (d, J=7.0 Hz, 3H);[α]^(D) ₂₀=−75.4° (±0.84°).

108.2(3R,4R)-4-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidinehydrochloride

Preparation as described for example “A32” (step 32.3).

108.3(R)-3,3,3-Trifluoro-1-{(3R,4R)-4-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A108”)

Preparation and purification as described for example “A32” (step 32.4);yield: 304 mg (94%) yellow foam; (purity 100%, Rt: 2.11 min, (M+H)400.1); HPLC (Chiralpak AD-H; CO₂/MeOH-95/5): Rt 2.00 min.

(R)-1-{4-[1-(3,5-Difluoro-pyridin-2-yl)-1H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A109”)

Purification by RP-flash chromatography (CombiFlashRF 200); yield: 30 mg(13%) colorless solid; (purity 100%, Rt: 2.05 min, (M+H) 405.1); ¹H NMR(500 MHz, DMSO-d₆, 90° C.) δ [ppm] 8.51 (d, J=2.4 Hz, 1H), 8.32 (dd,J=2.6, 0.9 Hz, 1H), 8.28 (ddd, J=10.8, 8.4, 2.5 Hz, 1H), 7.11 (s, 1H),6.55 (d, J=2.6 Hz, 1H), 4.89-4.35 (m, 2H), 3.34-3.13 (m, 1H), 3.12-3.00(m, 1H), 2.98-2.78 (m, 1H), 2.08-1.97 (m, 2H), 1.77-1.53 (m, 5H).

(R)-3,3,3-Trifluoro-1-{(3S,4S)-4-[2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A110”)

Preparation and purification as described for example “A32” (step 32.4);yield: 36 mg (53%) colorless solid; (purity 100%, Rt: 2.08 min, (M+H)412.1); ¹H NMR (400 MHz, DMSO-d₆, 90° C.) δ [ppm] 7.49 (d, J=1.9 Hz,1H), 7.42-7.23 (m, 2H), 7.17-6.93 (m, 2H), 6.69 (s, 1H), 6.22 (d, J=1.9Hz, 1H), 4.49 (d, J=13.2 Hz, 1H), 4.29-4.04 (m, 1H), 3.83 (s, 3H),3.27-3.06 (m, 2H), 2.96-2.83 (m, 1H), 2.01-1.81 (m, 1H), 1.81-1.61 (m,2H), 1.53 (d, J=1.2 Hz, 3H), 0.61 (d, J=7.0 Hz, 3H).

4-{5-[(3S,4S)-3-Methyl-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionyl)piperidin-4-yl]-pyrazol-1-yl}-benzonitrile(“A111”)

Preparation and purification as described for example “A32” (step 32.4);yield: 32 mg (56%) colorless solid; (purity 100%, Rt: 2.06 min, (M+H)407.1); ¹H NMR (400 MHz, DMSO-d₆, 90° C.) δ [ppm] 7.95 (d, J=8.5 Hz,2H), 7.70 (d, J=8.6 Hz, 2H), 7.63 (d, J=1.7 Hz, 1H), 6.70 (s, 1H), 6.33(d, J=1.6 Hz, 1H), 4.66-4.46 (m, 1H), 4.24-4.12 (m, 1H), 3.34 (dt,J=11.1, 4.2 Hz, 1H), 3.18-3.05 (m, 1H), 3.04-2.88 (m, 1H), 2.00-1.85 (m,1H), 1.80-1.64 (m, 2H), 1.53 (s, 3H), 0.58 (d, J=7.0 Hz, 3H).

(2R)-1-[4-[2-(5-Fluoro-2-pyridyl)-2H-pyrazol-3-yl]-1-piperidyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A112”)

Purification by RP-flash chromatography (CombiFlashRF 200); yield: 189.5mg (87%) colorless solid; (purity 100%, Rt: 2.09 min, (M+H) 387.1); ¹HNMR (500 MHz, DMSO-d₆) δ [ppm] 8.52 (d, J=3.0 Hz, 1H), 7.99-7.91 (m,1H), 7.85 (dd, J=9.0, 4.0 Hz, 1H), 7.65 (d, J=1.7 Hz, 1H), 7.03 (s, 1H),6.39 (s, 1H), 4.96-4.32 (m, 2H), 3.76-3.59 (m, 1H), 3.20-2.53 (m, 2H),2.02-1.89 (m, 2H), 1.68-1.32 (m, 5H).

(R)-3,3,3-Trifluoro-1-{(3S,4S)-4-[2-(6-methoxy-pyridin-3-yl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A113”)

Preparation and purification as described for example “A32” (step 32.4);yield: 68 mg (77%) colorless solid; (purity 100%, Rt: 1.97 min, (M+H)413.1); ¹H NMR (400 MHz, DMSO-d₆, 90° C.) δ [ppm] 8.23 (d, J=2.3 Hz,1H), 7.76 (dd, J=8.7, 2.7 Hz, 1H), 7.56 (d, J=1.7, 1H), 6.94 (d, J=8.7Hz, 1H), 6.70 (brs, 1H), 6.27 (d, J=1.7 Hz, 1H), 4.58-4.43 (m, 1H),4.21-4.09 (m, 1H), 3.94 (s, 3H), 3.23-2.87 (m, 3H), 2.00-1.82 (m, 1H),1.80-1.64 (m, 2H), 1.59-1.46 (m, 3H), 0.63 (d, J=7.0 Hz, 3H).

(R)-3,3,3-Trifluoro-2-hydroxy-1-[4-(1-isobutyl-1H-pyrazol-3-yl)-piperidin-1-yl]-2-methyl-propan-1-one(“A114”)

The synthesis of “A76” also provided a regioisomer, which was separatedby preparative HPLC; yield: 42 mg (11%) pale brown gum; (purity 96.0%,Rt: 3.77 min, (M+H) 348.3); ¹H NMR (400 MHz, CDCl₃): δ [ppm] 7.28-7.27(m, 1H), 6.03 (d, J=2.2 Hz, 1H), 5.57 (brs, 1H), 4.60-4.45 (m, 2H), 3.87(d, J=7.3 Hz, 2H), 3.14-3.12 (m, 2H), 3.04-2.96 (m, 1H), 2.21-2.14 (m,1H), 2.09-2.02 (m, 2H), 1.73-1.68 (m, 5H), 0.90 (d, J=6.80 Hz, 6H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[2-(5-methyl-isoxazol-3-yl)-2H-pyrazol-3-yl]-piperidin-1-yl}-propan-1-one(“A115”)

Purification by flash column chromatography; yield: 75 mg (23%) browngum; (purity 99.4%, Rt: 3.92 min, (M+H) 373.0); ¹H NMR (400 MHz,MeOH-d₄) δ [ppm] 7.68 (d, J=2.0 Hz, 1H), 6.54 (d, J=1.2 Hz, 1H), 6.38(d, J=1.6 Hz, 1H), 5.09-5.07 (m, 1H), 4.63-4.60 (m, 1H), 3.72-3.66 (m,1H), 3.15-3.13 (m, 1H), 2.80-2.78 (m, 1H), 2.49 (s, 3H), 2.12-2.09 (m,2H), 1.72-1.63 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[2-(tetrahydro-pyran-4-yl)-2H-pyrazol-3-yl]-piperidin-1-yl}-propan-1-one(“A116”)

Purification by prep. HPLC and finally by trituration with hexane;yield: 120 mg (28%) off-white solid; (purity 99.1%, Rt: 3.09 min, (M+H)376.3); ¹H NMR (400 MHz, DMSO-d₆) 5 [ppm] 7.35 (d, J=1.4 Hz, 1H), 7.08(s, 1H), 6.02 (s, 1H), 4.80-4.78 (m, 1H), 4.47-4.41 (m, 2H), 3.96-3.92(m, 2H), 3.50 (t, J=11.6 Hz, 2H), 3.15-3.06 (m, 2H), 2.73-2.66 (m, 1H),2.12-2.01 (m, 2H), 1.87-1.84 (m, 2H), 1.73-1.71 (m, 2H), 1.52-1.40 (m,5H).

(R)-1-[4-(2-Benzothiazol-2-yl-2H-pyrazol-3-yl)-piperidin-1-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A117”)

Purification by column chromatography; yield: 150 mg (49%) off-whitesolid; (purity 99.1%, Rt: 5.10 min, (M+H) 425.2); ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 8.08 (d, J=7.2 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.83(d, J=1.6 Hz, 1H), 7.54-7.50 (m, 1H), 7.44-7.40 (m, 1H), 7.11 (s, 1H),6.55 (s, 1H), 4.87-4.85 (m, 1H), 4.55-4.53 (m, 1H), 4.05-4.03 (m, 1H),3.20-3.18 (m, 1H), 2.77-2.75 (m, 1H), 2.17-2.15 (m, 2H), 1.70-1.55 (m,5H).

(R)-3,3,3-Trifluoro-1-{(3S,4S)-4-[2-(5-fluoro-pyridin-2-yl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A118”)

Preparation and purification as described for example “A32” (step 32.4);yield: 63 mg (77%) colorless solid; (purity 100%, Rt: 2.16 min, (M+H)401.1); ¹H NMR (400 MHz, DMSO-d₆, 90° C.) δ [ppm] 8.49 (d, J=2.9 Hz,1H), 7.91 (td, J=8.5, 2.9 Hz, 1H), 7.85 (dd, J=9.0, 4.2 Hz, 1H), 7.64(d, J=1.5 Hz, 1H), 6.73 (s, 1H), 6.34/6.32 (2×d, J=1.5 Hz, 1H,ratio=10:1, mixture of rotamers), 4.74-4.61 (m, 1H), 4.43-4.26 (m, 1H),3.99-3.88 (m, 1H), 3.11-2.95 (m, 2H), 2.23-2.11 (m, 1H), 2.09-1.91 (m,1H), 1.79-1.67 (m, 1H), 1.60/1.58 (2×s, 3H, ratio=10:1, mixture ofrotamers), 0.71-0.61 (m, 3H).

(R)-1-{(3S,4S)-4-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A119”)

Preparation and purification as described for example “A32” (step 32.4);yield: 140 mg (88%) colorless solid; (purity 99.5%, Rt: 2.25 min, (M+H)416.1-418.1); ¹H NMR (400 MHz, DMSO-d₆) δ ppm] 7.69-7.56 (m, 3H),7.57-7.47 (m, 2H), 7.13-6.84 (m, 1H), 6.51-6.11 (m, 1H), 4.98-3.95 (m,2H), 3.30-2.62 (m, 3H), 2.04-1.79 (m, 1H), 1.79-1.61 (m, 2H), 1.52 (s,3H), 0.71-0.41 (m, 3H).

(R)-3,3,3-Trifluoro-2-hydroxy-1-{(3S,4S)-4-[2-(4-hydroxy-cyclohexyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-2-methyl-propan-1-one(“A120”)

Preparation and purification as described for example “A32” (step 32.4);yield: 28 mg (73%) colorless solid; (purity 100%, Rt: 1.75 min, (M+H)404.2); ¹H NMR (400 MHz, DMSO-d₆, 90° C.) δ [ppm] 7.33 (d, J=1.6 Hz,1H), 6.74 (s, 1H), 5.96 (d, J=1.6 Hz, 1H), 4.70-4.51 (m, 1H), 4.42-4.30(m, 1H), 4.19-4.04 (m, 2H), 3.96-3.84 (m, 1H), 3.30-3.10 (m, 3H),2.44-2.20 (m, 2H), 2.12-2.00 (m, 1H), 2.00-1.75 (m, 3H), 1.70-1.61 (m,3H), 1.58 (s, 3H), 1.55-1.43 (m, 2H), 0.66 (d, J=7.0 Hz, 3H).

(R)-3,3,3-Trifluoro-2-hydroxy-1-{(3S,4S)-4-[2-(4-hydroxy-cyclohexyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-2-methyl-propan-1-one(“A121”)

Preparation and purification as described for example “A32” (step 32.4);yield: 18 mg (63%) colorless solid; (purity 96%, Rt: 1.71 min, (M+H)404.2); ¹H NMR (400 MHz, DMSO-d₆, 90° C.) δ [ppm] 7.32 (d, J=1.7 Hz,1H), 6.74 (s, 1H), 5.96 (d, J=1.7 Hz, 1H), 4.68-4.53 (m, 1H), 4.40-4.32(m, 1H), 4.32-4.24 (m, 1H), 4.19-4.07 (m, 1H), 3.60-3.46 (m, 1H),3.29-3.20 (m, 2H), 3.20-3.09 (m, 1H), 2.11-1.84 (m, 6H), 1.82-1.68 (m,2H), 1.68-1.60 (m, 1H), 1.60-1.55 (m, 3H), 1.50-1.34 (m, 2H), 0.65 (d,J=7.0 Hz, 3H).

(R)-3,3,3-Trifluoro-2-hydroxy-1-[4-(2-isoxazol-3-yl-2H-pyrazol-3-yl)-piperidin-1-yl]-2-methyl-propan-1-one(“A122”)

Purification by prep. HPLC; yield: 180 mg (68%) pale brown gum; (purity98.8%, Rt: 3.68 min, (M+H) 359.0); ¹H NMR (400 MHz, DMSO-d₆) δ [ppm]9.06 (d, J=1.8 Hz, 1H), 7.77 (d, J=1.7 Hz, 1H), 7.08 (s, 1H), 6.98 (d,J=1.8 Hz, 1H), 6.46 (d, J=Hz, 1H), 4.82-4.80 (m, 1H), 4.48-4.46 (m, 1H),3.60-3.54 (m, 1H), 3.16-3.14 (m, 1H), 2.67-2.66 (m, 1H), 1.97-1.95 (m,2H), 1.60-1.45 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(2-pyridazin-3-yl-2H-pyrazol-3-yl)piperidin-1-yl]-propan-1-one(“A123”)

Purification by flash column chromatography; yield: 28 mg (40%)off-white solid; (purity 96.6%, Rt: 3.11 min, (M+H) 370.0); ¹H NMR (400MHz, DMSO-d₆) δ [ppm] 9.20 (dd, J=4.76, 1.4 Hz, 1H), 8.10 (dd, J=8.9,1.4 Hz, 1H), 7.88 (dd, J=8.9, 4.8 Hz, 1H), 7.76 (d, J=1.7 Hz, 1H), 6.47(s, 1H), 4.77-4.75 (m, 1H), 4.44-4.42 (m, 1H), 3.82-3.78 (m, 1H),3.06-2.99 (m, 1H), 2.78-2.76 (m, 1H), 2.01-1.98 (m, 2H), 1.57-1.50 (m,5H).

(R)-3,3,3-Trifluoro-1-{4-[3-(4-fluoro-phenyl)-3H-imidazol-4-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A124”)

Preparation as described for example “A65”; yield: 30 mg (21%) off-whitesolid; (purity 97.8%, Rt: 2.90 min, (M+H) 386.2); ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 7.68 (s, 1H), 7.53-7.50 (m, 2H), 7.42-7.38 (m, 2H),7.03 (s, 1H), 6.86 (s, 1H), 4.89-4.55 (m, 1H), 4.49-4.23 (m, 1H),3.02-2.86 (m, 1H), 2.80-2.76 (m, 1H), 1.75-1.71 (m, 2H), 1.57-1.29 (m,6H).

(R)-1-{4-[3-(4-Chloro-phenyl)-3H-imidazol-4-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A125”)

Preparation as described for example “A65”; yield: 27 mg (18.5%)off-white solid; (purity 94.1%, Rt: 3.22 min, (M+H) 402.0-404.0); ¹H NMR(400 MHz, DMSO-d₆) δ [ppm] 7.70 (d, J=0.8 Hz, 1H), 7.63-7.61 (m, 2H),7.51-7.48 (m, 2H), 7.03 (s, 1H), 6.87 (s, 1H), 4.80-4.60 (m, 1H),4.47-4.29 (m, 1H), 3.02-2.89 (m, 1H), 2.84-2.77 (m, 1H), 1.79-1.62 (m,2H), 1.60-1.34 (m, 6H).

(R)-1-{4-[3-(4-Chloro-2-fluoro-phenyl)-3H-imidazol-4-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A126”)

Preparation as described for example “A65”; yield: 15 mg (9%) off-whitesolid; (purity 99.1%, Rt: 3.19 min, (M+H) 420.0-422.0); ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 7.78-7.75 (m, 1H), 7.69 (s, 1H), 7.60 (t, J=8.4 Hz,1H), 7.48 (d, J=8.5 Hz, 1H), 7.12 (s, 1H), 6.89 (s, 1H), 4.71-4.69 (m,1H), 4.39-4.38 (m, 1H), 3.03-2.90 (m, 1H), 2.63-2.55 (m, 1H), 1.79-1.62(m, 2H), 1.59-1.30 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[3-(4-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-piperidin-1-yl}-propan-1-one(“A127”)

Preparation as described for example “A65”; yield: 27 mg (13.5%)off-white solid; (purity 97.5%, Rt: 3.46 min, (M+H) 436.2); ¹H NMR (400MHz, DMSO-d₆) δ [ppm] 7.94 (d, J=8.4 Hz, 2H), 7.79 (s, 1H), 7.71 (d,J=8.0 Hz, 2H), 7.03 (s, 1H), 6.92 (s, 1H), 4.79-4.56 (m, 1H), 4.49-4.22(m, 1H), 3.05-2.83 (m, 2H), 2.63-2.52 (m, 1H), 1.81-1.65 (m, 2H),1.59-1.39 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(3-phenyl-isoxazol-4-yl)-piperidin-1-yl]-propan-1-one(“A128”) 128.1 4-(3-Phenyl-isoxazol-4-yl)-piperidine-1-carboxylic acidtert-butyl ester

In a microwave vessel 1-Boc-4-ethynylpiperidine (100.0 mg; 0.468 mmol)and (Z)—N-hydroxybenzimidoyl chloride (88.4 mg; 0.515 mmol) weredissolved in dry 1,2-dichloroethane (4.50 mL), triethylamine (81.1 μl;0.585 mmol) was added and the mixture was degassed with nitrogen.Chloro(1,5-cyclooctadiene)(pentamethylcyclopentadienyl)ruthenium (9.17mg; 0,023 mmol) was added to the colorless suspension. The reaction wasagain degassed with nitrogen and stirred at room temperature for 14 h.The reaction mixture was evaporated and the residue purified by flashchromatography (CombiFlashRF 200); yield: 122 mg (78%) yellow oil.

128.2 4-(3-Phenyl-isoxazol-4-yl)-piperidine hydrochloride

HCl in dioxane (4.0 M; 4.58 mL; 18.315 mmol) was added to4-(3-phenyl-isoxazol-4-yl)-piperidine-1-carboxylic acid tert-butyl ester(122.0 mg; 0.366 mmol) in dry 1,4-dioxane (4.54 mL; 53.112 mmol) andstirred for 14 h at room temperature. The reaction mixture wasconcentrated in vacuo and the residue was used without furtherpurification.

128.3(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(3-phenyl-isoxazol-4-yl)piperidin-1-yl]-propan-1-one(“A128”)

The coupling reaction was performed as described above; yield: 79 mg(58%) colorless solid; (purity 99.1%, Rt: 2.21 min, (M+H) 369.1); ¹H NMR(400 MHz, DMSO-d₆) δ [ppm] 8.88 (d, J=0.7 Hz, 1H), 7.68-7.59 (m, 2H),7.59-7.48 (m, 3H), 7.00 (s, 1H), 4.92-4.56 (m, 1H), 4.56-4.16 (m, 1H),3.22-2.95 (m, 1H), 2.95-2.84 (m, 1H), 2.84-2.56 (m, 1H), 1.93-1.74 (m,2H), 1.61-1.31 (m, 5H).

(R)-3,3,3-Trifluoro-1-{⁴-[3-(4-fluoro-phenyl)-isoxazol-4-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A129”)

Preparation as described for “A126”; yield: 61 mg (37%) colorless solid;(purity 98.0%, Rt: 2.25 min, (M+H) 387.1); ¹H NMR (400 MHz, DMSO-d₆) δ[ppm] 8.96-8.78 (m, 1H), 7.78-7.60 (m, 2H), 7.46-7.27 (m, 2H), 7.00 (s,1H), 4.89-4.57 (m, 1H), 4.57-4.21 (m, 1H), 3.25-2.93 (m, 1H), 2.93-2.83(m, 1H), 2.83-2.53 (m, 1H), 1.92-1.75 (m, 2H), 1.61-1.30 (m, 5H).

(R)-1-{4-[3-(2,4-Difluoro-phenyl)-3H-imidazol-4-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A130”)

Preparation as described for example “A65”; yield: 2 mg (2%) off-whitesolid; (purity 94.6%, Rt: 2.91 min, (M+H) 404.2); ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 7.69-7.58 (m, 3H), 7.32-7.27 (m, 1H), 7.04 (s, 1H),6.88 (s, 1H), 4.80-4.50 (m, 1H), 4.49-4.20 (m, 1H), 3.08-2.82 (m, 1H),2.63-2.53 (m, 2H), 1.72-1.60 (m, 2H), 1.56-1.37 (m, 5H).

(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[3-(4-methoxy-phenyl)-3H-imidazol-4-yl]-piperidin-1-yl}-2-methyl-propan-1-one (“A131”)

Preparation as described for example “A65”; yield: 12 mg (15%) off-whitesolid; (purity 94.3%, Rt: 2.97 min, (M+H) 398.0); ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 7.60 (s, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.8Hz, 2H), 7.02 (s, 1H), 6.82 (brs, 1H), 4.76-4.51 (m, 1H), 4.45-4.20 (m,1H), 3.81 (s, 3H), 3.03-2.83 (m, 1H), 2.85-2.60 (m, 1H), 1.79-1.61 (m,2H), 1.57-1.29 (m, 6H).

(R)-3,3,3-Trifluoro-1-{4-[3-(2-fluoro-phenyl)-3H-imidazol-4-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A132”)

Preparation as described for example “A65”; yield: 9 mg (2%) off-whitesolid; (purity 97.1%, Rt: 2.76 min, (M+H) 386.0); ¹H NMR (400 MHz,DMSO-de) δ [ppm] 7.71 (s, 1H), 7.63-7.49 (m, 3H), 7.41-7.37 (m, 1H),7.02 (s, 1H), 6.90 (s, 1H), 4.80-4.52 (m, 1H), 4.45-4.21 (m, 1H),3.06-2.83 (m, 2H), 2.63-2.59 (m, 1H), 1.78-1.60 (m, 2H), 1.59-1.32 (m,5H).

(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[3-(6-methoxy-pyridin-3-yl)-3H-imidazol-4-yl]-piperidin-1-yl}-2-methyl-propan-1-one(“A133”)

Preparation as described for example “A65”; yield: 20 mg (18%) off-whitesolid; (purity 99.6%, Rt: 2.67 min, (M+H) 399.0); ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 8.27 (d, J=2.5 Hz, 1H), 7.84 (dd, J=8.7, 5.7 Hz, 1H),7.69 (s, 1H), 7.03 (s, 1H), 6.99 (d, J=8.8 Hz, 1H), 6.88 (s, 1H),4.78-4.60 (m, 1H), 4.44-4.25 (m, 1H), 3.91 (s, 3H), 3.10-2.88 (m, 2H),2.80-2.70 (m, 1H), 1.80-1.65 (m, 2H), 1.60-1.32 (m, 5H).

(R)-3,3,3-Trifluoro-1-{4-[3-(2-fluoro-4-methoxy-phenyl)-3H-imidazol-4-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one(“A134”)

Preparation as described for example “A65”; yield: 20 mg (13%) off-whitesolid; (purity 96.7%, Rt: 2.99 min, (M+H) 416.2); ¹H NMR (400 MHz,DMSO-d₆) δ [ppm] 7.63 (s, 1H), 7.48-7.44 (m, 1H), 7.13 (dd, J=12.0, 7.4Hz, 1H), 7.03 (s, 1H), 6.93 (dd, J=8.4, 5.6 Hz, 1H), 6.87 (s, 1H),4.80-4.58 (m, 1H), 4.50-4.29 (m, 1H), 3.84 (s, 3H), 3.08-2.88 (m, 1H),2.62-2.52 (m, 2H), 1.72-1.69 (m, 2H), 1.60-1.33 (m, 5H).

(2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrazol-3-yl]-1-piperidyl]propan-1-one(“A135”)

(2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(2-methylthiazol-5-yl)pyrazol-3-yl-1-piperidyl]propan-1-one(“A136”)

(2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(5-methyl-1,3,4-thiadiazol-2-yl)pyrazol-3-yl]-1-piperidyl]propan-1-one(“A137”)

(2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(5-methyl-1,3,4-oxadiazol-2-yl)pyrazol-3-yl]-1-piperidyl]propan-1-one(“A138”)

(2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(2-methylpyrimidin-5-yl)pyrazo]-3-yl]-1-piperidyl]propan-1-one(“A139”)

(2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(2-methylthiazol-4-yl)pyrazol-3-yl]-1-piperidyl]propan-1-one(“A140”)

(2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(5-methylpyrazin-2-yl)pyrazol-3-yl]-1-piperidyl]propan-1-one(“A141”)

(2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(1-methylimidazol-2-yl)pyrazol-3-yl]-1-piperidyl]propan-1-one(“A142”)

(2R)-1-[4-[2-[4-(1,1-Difluoroethyl)phenyl]pyrazol-3-yl]-1-piperidyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one (“A143”)

(2R)-1-[(3S,4S)-4-[2-(3,5-Difluoro-2-pyridyl)pyrazol-3-yl]-3-methyl-1-piperidyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A144”)

(2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[(3S,4S)-3-methyl-4-[2-(1-methylpyrazol-4-yl)pyrazol-3-yl]-1-piperidyl]propan-1-one(“A145”)

(2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)pyrazol-3-yl]-1-piperidyl]propan-1-one(“A146”)

(2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[(3S,4S)-3-methyl-4-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)pyrazol-3-yl]-1-piperidyl]propan-1-one(“A147”)

(2R)-3,3,3-Trifluoro-2-hydroxy-1-[(3S,4S)-4-[2-[4-(1-hydroxy-1-methyl-ethyl)phenyl]pyrazol-3-yl]-3-methyl-1-piperidyl]-2-methyl-propan-1-one(“A148”)

(2R)-3,3,3-Trifluoro-1-[(3R,4S)-4-[3-(4-fluorophenyl)-1,2,4-triazol-4-yl]-3-methyl-1-piperidyl]-2-hydroxy-2-methyl-propan-1-one(“A149”)

(2R)-1-[(3R,4S)-4-[3-(2,4-Difluorophenyl)-1,2,4-triazol-4-yl]-3-methyl-1-piperidyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one(“A150”)

(2R)-3,3,3-trifluoro-2-hydroxy-1-[4-[3-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-imidazol-4-yl]-1-piperidyl]-2-methyl-propan-1-one(“A151”)

(2R)-3,3,3-Trifluoro-1-[(3S,4S)-4-[3-(4-fluorophenyl)imidazol-4-yl]-3-methyl-1-piperidyl]-2-hydroxy-2-methyl-propan-1-one(“A152”)

(2R)-3,3,3-Trifluoro-1-[4-[3-(4-fluorophenyl)-2-methyl-imidazol-4-yl]-1-piperidyl]-2-hydroxy-2-methyl-propan-1-one(“A153”)

(2R)-3,3,3-Trifluoro-1-[4-[3-(4-fluorophenyl)-2-(hydroxymethyl)imidazol-4-yl]-1-piperidyl]-2-hydroxy-2-methyl-propan-1-one(“A154”)

(2R)-3,3,3-trifluoro-1-[4-[3-(4-fluorophenyl)-2-methoxy-imidazol-4-yl]-1-piperidyl]-2-hydroxy-2-methyl-propan-1-one(“A155”)

Pharmacological Data

TABLE 1 Inhibition of PDHK of some representative compounds of theformula I Compound IC₅₀ PDHK2 Binding (ITC) IC₅₀ No. (enzyme assay) KD(cell data) “A1 ” A A B “A2” A A B “A3” B B “A4” A A B “A5” B A B “A6” BA B “A7” B A “A8” B A B “A9” B A B “A10” A A B “A11” A A B “A12” B A C“A13” A A B “A14” A A B “A15” A A A “A16” A A B “A17” B A B “A18” A A B“A19” B A B “A20” A A B “A21” B A B “A22” B A B “A23” A A B “A24” A A B“A25” B A B “A26” A A B “A27” A A B “A28” A A B “A29” B B “A30” A A B“A31” A A A “A32” A B “A33” A A “A34” B B “A35” A A B “A36” B A C “A37”B A C “A38” B A B “A39” A A B “A40” B “A41” A A B “A42” B A B “A43” B AB “A44” B A B “A45” C “A46” A A B “A47” C “A48” A A B “A49” A A B “A50”A A “A51” B “A52” B B “A53” B A B “A54” B B C “A55” B B C “A56” B B“A57” B B C “A58” B B “A59” B “A60” B B “A61” A A C “A62” A A B “A63” BA C “A64” A A B “A65” B A B “A66” B B “A67” B B “A68” B B “A69” B “A70”B B “A71” B B “A72” B B “A73” B “A74” B A “A75” C “A76” C “A77” C B C“A78” B A C “A79” “A80” B A C “A81” B “A82” A A B “A83” B A B “A84” B“A85” B A C “A86” B A C “A87” “A88” B A B “A89” B “A90” B “A91” B A C“A92” B A B “A93” “A94” B A C “A95” A A B “A96” B A B “A97” A A B “A98”A A B “A99” C “A100” B A B “A101” B A B “A102” C B C “A103” C “A104” C“A105” B B “A106” A A A “A107” A A A “A108” B B “A109” B “A110” A A A“A111” A A A “A112” B A C “A113” A A A “A114” B “A115” B A C “A116” B BC “A117” B A C “A118” A A B “A119” A A A “A120” A A B “A121” A A B“A122” B B “A123” “A124” B A B “A125” B A B “A126” A A B “A127” B A B“A128” B A C “A129” B A C “A130” B A B “A131” B A B IC₅₀: <0.3 μM = A0.3-3 μM = B 3-50 μM = C

The compounds shown in Table 1 are particularly preferred compoundsaccording to the invention.

The following examples relate to medicaments:

Example A Injection Vials

A solution of 100 g of an active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2 N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions.

Each injection vial contains 5 mg of active ingredient.

Example B Suppositories

A mixture of 20 g of an active ingredient of the formula I with 100 g ofsoya lecithin and 1400 g of cocoa butter is melted, poured into mouldsand allowed to cool. Each suppository contains 20 mg of activeingredient.

Example C Solution

A solution is prepared from 1 g of an active ingredient of the formulaI, 9.38 g of NaH₂PO₄.2 H₂O, 28.48 g of Na₂HPO₄.12 H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

Example D Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

Example E Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active ingredient.

Example F Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

Example G Capsules

2 kg of active ingredient of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

Example H Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

1: A compound, wherein the compound is a compound of formula I or apharmaceutically acceptable salt, tautomer or stereoisomer thereof,wherein formula (I) is

wherein R denotes pyrazol-diyl, imidazol-diyl, isoxazol-diyl ortriazol-diyl, each of which is unsubstituted or monosubstituted by R²,R¹ denotes (CH₂)_(n)Ar, (CH₂)_(n)Het, A or Cyc, R² denotes A′, methoxy,hydroxy methyl, COOA′, CN, COOH, CONH₂ or OH, R³ denotes H, A′, COOA′ orCN, Ar denotes phenyl, which is unsubstituted or mono-, di-, tri-,tetra- or pentasubstituted by Hal, A, CN, OA, [C(R⁵)₂]_(p)OH,[C(R⁵)₂]_(p)N(R⁵)₂, NO₂, [C(R⁵)₂]_(p)COOR⁵, NR⁵COA, NR⁵SO₂A,[C(R⁵)₂]_(p)SO₂N(R⁵)₂, S(O)_(n)A, O[C(R⁵)₂]_(m)N(R⁵)₂, NR⁵COOA,NR⁵CON(R⁵)₂ and/or COA, Het denotes a mono- or bicyclic saturated,unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms,which is unsubstituted or mono- or disubstituted by Hal, A, CN, OA,[C(R⁵)₂]_(p)OH, [C(R⁵)₂]_(p)N(R⁵)₂, NO₂, [C(R⁵)₂]_(p)COOR⁵, NR⁵COA,NR⁵SO₂A, [C(R⁵)₂]_(p)SO₂N(R⁵)₂, S(O)_(n)A, O[C(R⁵)₂]_(m)N(R⁵)₂, NR⁵COOA,NR⁵CON(R⁵)₂ and/or COA, Cyc denotes cyclic alkyl with 3, 4, 5, 6 or 7C-atoms, which is unsubstituted or monosubstituted by OH, A denotesunbranched or branched alkyl with 1-10 C-atoms, wherein one or twonon-adjacent CH- and/or CH₂-groups are optionally replaced by N-, O-and/or S-atoms and/or wherein 1-7 H-atoms are optionally replaced by R⁴,R⁴ denotes F, Cl or OH, R⁵ denotes H or A′, A′ denotes unbranched orbranched alkyl with 1-6 C-atoms, wherein 1-5H-atoms are optionallyreplaced by F, Hal denotes F, Cl, Br or I, m denotes 1, 2, 3 or 4, ndenotes 0, 1 or 2, and p denotes 0, 1, 2, 3 or
 4. 2: The compoundaccording to claim 1, wherein R² denotes A′, methoxy or hydroxymethyl.3: The compound according to claim 1, wherein R³ denotes H or A′. 4: Thecompound according to claim 1, wherein Ar denotes phenyl, which isunsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal, A,CN and/or OA. 5: The compound according to claim 1, wherein Het denotespyrimidyl, pyridyl, pyridazinyl, pyrazinyl, piperidinyl, pyrrolidinyl,pyrazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, pyrrolyl,oxazolyl, isoxazolyl, triazolyl, oxadiazolyl or thiadiazolyl, each ofwhich is unsubstituted or mono- or disubstituted by Hal, A, CN and/orOA. 6: The compound according to claim 1, wherein R denotespyrazol-diyl, imidazol-diyl, isoxazol-diyl or triazol-diyl, each ofwhich is unsubstituted or monosubstituted by R², R¹ denotes (CH₂)_(n)Ar,(CH₂)_(n)Het, A or Cyc, R² denotes A′, methoxy or hydroxymethyl, R³denotes H or A′, Ar denotes phenyl, which is unsubstituted or mono-,di-, tri-, tetra- or pentasubstituted by Hal, A, CN and/or OA, Hetdenotes pyrimidyl, pyridyl, pyridazinyl, pyrazinyl, piperidinyl,pyrrolidinyl, pyrazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl,pyrrolyl, oxazolyl, isoxazolyl, triazolyl, oxadiazolyl or thiadiazolyl,each of which is unsubstituted or mono- or disubstituted by Hal, A, CNand/or OA, Cyc denotes cyclic alkyl with 3, 4, 5, 6 or 7 C-atoms, whichis unsubstituted or monosubstituted by OH, A denotes unbranched orbranched alkyl with 1-10 C-atoms, wherein one or two non-adjacent CH-and/or CH₂-groups are optionally replaced by N-, O- and/or S-atomsand/or wherein 1-7 H-atoms are optionally replaced by R⁴, R⁴ denotes F,Cl or OH, A′ denotes unbranched or branched alkyl with 1-6 C-atoms,wherein 1-5H-atoms are optionally replaced by F, Hal denotes F, Cl, Bror I, and n denotes 0, 1 or
 2. 7: The compound according to claim 1,selected from the group consisting of No. Name “A1”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(2-p-tolyl-2H-pyrazol-3-yl)-piperidin-1-yl]-propan-1-one “A2”(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-methyl-propan-1-one “A3”2-{5-[1-((R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-pyrazol-1-yl}-benzonitrile “A4”(R)-3,3,3,Trifluoro-1-{4-[2-(2-fluoro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one “A5”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(2-o-tolyl-2H-pyrazol-3-yl)-piperidin-1-yl]-propan-1-one “A6”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(2-m-tolyl-2H-pyrazol-3-yl)-piperidin-1-yl]-propan-1-one “A7”(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[2-(2-methoxy-phenyl)-2H-pyrazol-3-yl)-piperidin-1-yl}-2-methyl-propan-1-one “A8”3-{5-[1-((R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-pyrazol-1-yl}-benzonitrile “A9”4-{5-[1-((R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-pyrazol-1-yl}-benzonitrile “A10”(R)-3,3,3-Trifluoro-1-{4-[2-(3-fluoro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one “A11”(R)-1-{4-[2-(2-Chloro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A12”(R)-1-{4-[2-(3-Chloro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A13”(R)-1-{4-[2(4-Chloro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A14”(R)-3,3,3-Trifluoro-1-{4-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one “A15”(R)-1-{4-[2-(3-Chloro-2-fluro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy- 2-methyl-propan-1-one “A16”(R)-3,3,3-Trifluoro-1-{4-[2-(2-fluoro-4-methyl-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one “A17”(R)-1-[4-(2-tert-Butyl-2H-pyrazol-3-yl)-piperidin-1-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A18”(R)-1-{4-[2-(2-Chloro-4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy- 2-methyl-propan-1-one“A19” (R)-1-{4-[2-(5-Bromo-pyrimidin-2-yl)- 2H-pyrazol-3-yl]-piperidin-1-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A20”(R)-3,3,3-Trifluoro-2-hydroxy-1-(4-{2-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-2H-pyrazol-3-yl}-piperidin-1-yl)-2-methyl- propan-1-one“A21” (R)-1-{4-[2-(4-tert-Butyl-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A22”(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[2-(4-isopropyl-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-methyl-propan-1-one “A23”(R)-1-{4-[2-(4-Chloro-2-fluoro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy- 2-methyl-propan-1-one “A24”(R)-1-{4-[2-(4-Ethyl-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A25”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(2-phenyl-2H-pyrazol-3-yl)-piperidin-1-yl]-propan-1-one “A26”(R)-1-{4-[2-(2,4-Difluoro-phenyl)- 2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A27”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]- piperidin-1-yl}-propan-1-one“A28” (R)-3,3,3-Trifluoro-1-{4-[2-(2-fluoro-4-methoxy-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one “A29”(R)-1-{4-[1-(5-Chloro-pyridin-2-yl)-1H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A30”rac-3,3,3-Trifluoro-1-{4-[2-(2-fluoro-4-methoxy-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one “A31”(R)-1-{4-[2-(2,4-Difluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy- 2-methyl-propan-1-one “A32”(R)-1-{(3R,4R)-4-[2-(2,4-difluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl- propan-1-one“A33” (R)-1-{(3S,4S)-4-[2-(2,4-difluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl- propan-1-one“A34” (R)-1-{4-[1-(4-Chloro-phenyl)-5-methyl-1H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy- 2-methyl-propan-1-one “A35”(R)-1-{4-[2-(4-Chloro-phenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A36”(R)-1-[4-(2-isopropyl-2H-pyrazol-3-yl)-piperidin-1-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A37”(R)-1-[4-(2-Cyclohexyl-2H-pyrazol-3-yl)-piperidin-1-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A38”(R)-1-[4-(2-Benzyl-2H-pyrazol-3-yl)-piperidin-1-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A39”(R)-1-{4-(2-(2-Chloro-4-fluoro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy- 2-methyl-propan-1-one “A40”(R)-1-{4-[1-(4-Fluoro-phenyl)-5-methyl-1H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy- 2-methyl-propan-1-one “A41”(R)-1-{4-[2-(4-Fluoro-phenyl)-5-methyl-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy- 2-methyl-propan-1-one “A42”(R)-1-{4-[2-(4-Fluoro-phenyl)-5-trifluoromethyl-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A43”(R)-1-[4-(2-Phenyl)-5-trifluoromethyl- 2H-pyrazol-3-yl)-piperidin-1-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A44”(R)-1-{4-[1-(4-Fluro-phenyl)-1H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy- 2-methyl-propan-1-one “A45”(R)-3,3,3-Trifluoro-1-{(3R,4R)-4-[1-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-2-hydroxy-2-methyl- propan-1-one“A46” (R)-3,3,3-Trifluoro-1-{(3S,4S)-4-[1-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-2-hydroxy-2-methyl- propan-1-one“A47” (R)-1-[4-(5-Methyl-1-phenyl-1H-pyrazol-3-yl)-piperidin-1-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A48”(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[2-(3-chloro-4-methoxy-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}- 2-methyl-propan-1-one “A49”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-(4-{2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-2H-pyrazol-3-yl}-piperidin-1-yl)- propan-1-one“A50” (R)-1-{4-[2-(4-Chloro-phenyl)-5-methyl-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy- 2-methyl-propan-1-one “A51”(R)-1-{4-[2-Cyclopentyl-2H-pyrazol-3-yl)-piperidin-1-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A52”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(2-methyl-2H-pyrazol-3-yl)-piperidin-1-yl]-propan-1-one “A53”(R)-3,3,3-Trifluoro-2-hydroxy-1- {4-[2-(6-methoxy-pyridin-3-yl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-methyl-propan-1-one “A54”5-(2-Fluoro-phenyl)-4-[1-((R-3,3,3-trifluoro-2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-2,4-dihydro-[1,2,4]triazol-3- one“A55” (R)-3,3,3-Trifluoro-1-{4-[3-(2-fluoro-phenyl)-[1,2,4]triazol-4-yl]-piperidin-1-yl]-2-hydroxy-2-methyl-propan-1-one “A56”(R)-1-{4-[3-(4-Chloro-phenyl)-[1,2,4]trizaol-4-yl]-piperidin-1-yl}-3,3,3-trifluoro- 2-hydroxy-2-methyl-propan-1-one“A57” (R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[3-(4-methoxy-phenyl)-3H-[1,2,3]triazol-4-yl]-piperidin-1-yl}-2-methyl-propan-1-one “A58”(R)-1-{4-[3-(4-Chloro-phenyl)-3H-[1,2,3]trizaol-4-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A59”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(3-p-tolyl-3H-[1,2,3]triazol-4-yl]-piperidin-1-yl]-propan-1-one “A60”(R)-3,3,3-Trifluoro-1-{4-[3-(2-fluoro-4-methyl-phenyl)-3H-[1,2,3]triazol-4-yl]-piperidin-1-yl}-2-hydroxy- 2-methyl-propan-1-one“A61” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(2-phenyl-imidazol-1-yl)-piperidin-1-yl]-propan-1-one “A62”(R)-1-{4-[2-(4-Chloro-phenyl)-imidazol-1-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A63”(2R)-3,3,3-trifluoro-2-hydroxy-2-methyl-1-[4-(5-phenylimidazol-1-yl)-1-piperidyl]propan-1-one “A64”(2R)-1-[4-[5-(4-chlorophenyl)imidazol-1-yl]-1-piperidyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A65”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(3-phenyl-3H-imidazol-4-yl)-piperidin-1-yl]-propan-1-one “A66”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(5-phenyl-pyrazol-1-yl)-1-piperidin-1-yl]-propan-1-one “A67”(R)-3,3,3-Trifluoro-1-{4-[1-(4-fluoro- phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one “A68”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(1-p-tolyl-1H-imidazol-2-yl)-piperidin-1-yl]-propan-1-one “A69”(R)-1-{4-[1-(4-Chloro-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A70”(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[1-(4-methoxy-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-2-methyl-propan-1-one “A71”(R)-3,3,3-Trifluoro-1-{4-[4-(4- fluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one “A72”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(4-phenyl-4H-[1,2,4]triazol-3-yl)-piperidin-1-yl]-propan-1-one “A73”(R)-1-{4-[4-(4-Chloro-phenyl)-4H-[1,2,4]triazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A74”(R)-1-[4-(2-Cyclopropyl-2H-pyrazol-3-yl)-1-piperidyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A75”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[2-(1-methyl-piperidin-4-yl)-2H-pyrazol-3-yl]-piperidin-1-yl}-propan-1-one “A76”(R)-3,3,3-Trifluoro-2-hydroxy-1-[4-(2-isobutyl-1H-pyrazol-3-yl)-1-piperidyl]-2-methyl-propan-1-one “A77”(R)-3,3,3-Trifluoro-2-hydroxy-2- methyl-1-{4-[2-(2,2,2-trifluoro-ethyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-propan-1-one “A78”(R)-3,3,3-Trifluoro-2-hydroxy-1-[4-[2-(2-methoxyethyl-2H-pyrazol-3-yl]-1-piperidyl]-2-methyl-propan-1-one “A79”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-1-piperidin-1-yl}-propan-1-one “A80”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-[6-(trifluoro-methyl)-3-pyridyl]-2H-pyrazol-3-yl]-1-piperidyl]propan-1-one “A81”5-{5-[1-((R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-pyrazol-1-yl}-1-piperidine-2-carbonitrile “A82”(R)-1-[4-[2-(3,5-Diflouro-2-pyridyl)-2H-pyrazol-3-yl]-1-piperidyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A83”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[2-(5-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]-piperidin-1-yl}-propan-1-one “A84”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(5-trifluoro-methyl-pyridin-2-yl)-2H-pyrazol-3-yl]- piperidin-1-yl}-propan-1-one“A85” (R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(1-methylpyrazol-4-yl)-2H-pyrazol-3-yl]-1- piperidyl]propan-1-one “A86”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(4-methylthiazol-2-yl)-2H-pyrazol-3-yl]-1-piperidyl]propan-1-one “A87”(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[2-(1H-imidazol-2-yl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-methyl-propan-1-one “A88”(R)-3,3,3-Trifluoro-1-[4-[2-[2-fluoro-4-(trifluoromethyl)phenyl]-2H-pyrazol-3-yl]-1-piperidyl]-2-hydroxy-2-methyl-propan-1-one “A89”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-[2-(trifluoro-methyl)phenyl]-2H-pyrazol-3-yl]-1-piperidyl]-propan-1-one “A90”(R)-3,3,3-Trifluoro-1-{4-[2-(4-fluoro-2-methoxy-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one “A91”3-Fluoro-4-[5-[1-[(R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propanoyl]-4-piperidyl]-2H-pyrazol-1-yl]benzonitrile “A92”(R)-3,3,3-Trifluoro-1-[4-[2-[2-fluoro-4-(1-hydroxy-1-methyl-ethyl)phenyl]-2H-pyrazol-3-yl]-1-piperidyl]-2-hydroxy-2-methyl-propan-1-one “A93”(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[2-(6-methoxy-pyridazin-3-yl)-2H-pyrazol-3-yl]-piperidin-1-yl}-2-methyl-propan-1-one “A94”(R)-3,3,3-Trifluoro-2-hydroxy-1-[4-[2-(4-hydroxycyclohexyl)-2H-pyrazol-3-yl]-piperidyl]-2-methyl-propan-1-one “A95”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[3-[4-(trifluoro-methoxy)-phenyl]-2H-pyrazol-3-yl]-piperidyl]-propan-1-one “A96”(R)-1-[4-[2-[4-(Difluoromethoxy)phenyl]-2H-pyrazol-3-yl]-1-piperidyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A97”(R)-1-{4-[2-(2,4-(Difluoro-phenyl)-5-methyl-2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy- 2-methyl-propan-1-one “A98”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(5-methyl-2-phenyl-2H-pyrazol-3-yl)-piperidin-1-yl]-propan-1-one “A99”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(1-methyl-1H-pyrazol-3-yl)-piperidin-1-yl]-propan-1-one “A100”(R)-1-{4-[2-(4-Chloro-3-fluoro-phenyl)-2H-pyrazol-3-yl]-piperidin-1-yl)-3,3,3-trifluoro-2-hydroxy- 2-methyl-propan-1-one “A101”(R)-1-{4-[2-(3,4-Dichloro-phenyl)- 2H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A102”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[1-(5-trifluoro-methyl-pyridin-2-yl)-1H-pyrazol-3-yl]- piperidin-1-yl}-propan-1-one“A103” (R)-1-{4-[1-(5-Chloro-pyrimidin-2-yl)-1H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A104”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(2H-pyrazol-3-yl)-piperidin-1-yl]-propan-1-one “A105”(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[1-(6-methoxy-pyridazin-3-yl)-1H-pyrazol-3-yl]-piperidin-1-yl}-2-methyl-propan-1-one “A106”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[(3S,4S)-3-methyl-4-(2-phenyl-2H-pyrazol-3-yl)-piperidin-1-yl]-propan-1-one “A107”(R)-3,3,3-Trifluoro-1-{(3S,4S)-4-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-2-hydroxy-2-methyl- propan-1-one“A108” (R)-3,3,3-Trifluoro-1-{(3R,4R)-4-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-2-hydroxy-2-methyl- propan-1-one“A109” (R)-1-{4-[1-(3,5-Difluoro-pyridin-2-yl)-1H-pyrazol-3-yl]-piperidin-1-yl}-3,3,3-trifluoro-2- hydroxy-2-methyl-propan-1-one “A110”(R)-3,3,3-Trifluoro-1-{(3S,4S)-4-[2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-2-hydroxy-2-methyl- propan-1-one“A111” 4-{5-[(3S,4S)-3-Methyl-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-pyrazol-1-yl}-benzonitrile “A112”(2R)-1-[4-[2-(5-Fluoro-2-pyridyl)-2H-pyrazol-3-yl]-1-piperidyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A113”(R)-3,3,3-Trifluoro-1-{(3S,4S)-4-[2-(6-methoxy-pyridin-3-yl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one “A114”(R)-3,3,3-Trifluoro-2-hydroxy-1-[4-(1-isobutyl-1H-pyrazol-3-yl)-piperidin-1-yl]-2-methyl-propan-1-one “A115”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[2-(5-methyl-isoxazol-3-yl)-2H-pyrazol-3-yl]-piperidin-1-yl}-propan-1-one “A116”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[2-(tetrahydro-pyran-4-yl)-2H-pyrazol-3-yl]-piperidin-1-yl}-propan-1-one “A117”(R)-1-[4-(2-Benzothiazol-2-yl-2H-pyrazol-3-yl)-piperidin-1-yl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A118”(R)-3,3,3-Trifluoro-1-{(3S,4S)-4-[2-(5-fluoro-pyridin-2-yl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-2-hydroxy-2-methyl- propan-1-one“A119” (R)-1-{(3S,4S)-4-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl- propan-1-one“A120” (R)-3,3,3-Trifluoro-2-hydroxy-1-{(3S,4S)-4-[2-(4-hydroxy-cyclohexyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-2-methyl-propan-1-one “A121”(R)-3,3,3-Trifluoro-2-hydroxy-1-{(3S,4S)-4-[2-(4-hydroxy-cyclohexyl)-2H-pyrazol-3-yl]-3-methyl-piperidin-1-yl}-2-methyl-propan-1-one “A122”(R)-3,3,3-Trifluoro-2-hydroxy-1-[4-(2-isoxazol-3-yl-2H-pyrazol-3-yl)-piperidin-1-yl]-2-methyl-propan-1-one “A123”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(2-pyridazin-3-yl-2H-pyrazol-3-yl)-piperidin-1-yl]-propan-1-one “A124”(R)-3,3,3-Trifluoro-1-{4-[3-(4-fluoro-phenyl)-3H-imidazol-4-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one “A125”(R)-1-{4-[3-(4-Chloro-phenyl)-3H- imidazol-4-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A126”(R)-1-{4-[3-(4-Chloro-2-fluoro-phenyl)-3H-imidazol-4-yl]-piperidin-1-yl}-3,3,3-trifluoro-2- hydroxy-2-methyl-propan-1-one “A127”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-{4-[3-(4-trifluoro-methyl-phenyl)-3H-imidazol-4-yl]-piperidin-1-yl}-propan-1-one “A128”(R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-(3-phenyl-isoxazol-4-yl)-piperidin-1-yl]-propan-1-one “A129”(R)-3,3,3-Trifluoro-1-{4-[3-(4-fluoro-phenyl)-isoxazol-4-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one “A130”(R)-1-{4-[3-(2,4-Difluoro-phenyl)- 3H-imidazol-4-yl]-piperidin-1-yl}-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A131”(R)-3,3,3-Trifluoro-2-hydroxy-1-{4-[3-(4-methoxy-phenyl)-3H-imidazol-4-yl]-piperidin-1-yl}-2-methyl-propan-1-one “A132”(R)-3,3,3-Trifluoro-1-{4-[3-(2- fluoro-phenyl)-3H-imidazol-4-yl]-piperidin-1-yl}-2-hydroxy-2-methyl-propan-1-one “A133”(R)-3,3,3-Trifluoro-2-hydroxy- 1-{4-[3-(6-methoxy-pyridin-3-yl)-3H-imidazol-4-yl]-piperidin-1-yl}-2-methyl-propan-1-one “A134”(R)-3,3,3-Trifluoro-1-{4-[3-(2-fluoro-4-methoxy-phenyl)-3H-imidazol-4-yl]-piperidin-1-yl}-2- hydroxy-2-methyl-propan-1-one “A135”(2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrazol-3-yl]-1-piperidyl]propan-1-one “A136”(2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(2-methylthiazol-5-yl)pyrazol-3-yl]-1-piperidyl]propan-1-one “A137”(2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(5-methyl-1,3,4-thiadiazol-2-yl)pyrazol-3-yl]-1-piperidyl]propan-1-one “A138”(2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(5-methyl-1,3,4-oxadiazol-2-yl)pyrazol-3-yl]-1-piperidyl]propan-1-one “A139”(2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(2-methylpyrimidin-5-yl)pyrazol-3-yl]-1-piperidyl]propan-1-one “A140”(2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(2-methylthiazol-4-yl)pyrazol-3-yl]-1-piperidyl]propan-1-one “A141”(2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(5-methylpyrazin-2-yl)pyrazol-3-yl]-1-piperidyl]propan-1-one “A142”(2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(1-methylimidazol-2-yl)pyrazol-3-yl]-1-piperidyl]propan-1-one “A143”(2R)-1-[4-[2-[4-(1,1-Difluoroethyl)phenyl]pyrazol-3-yl]-1-piperidin]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan-1-one “A144”(2R)-1-[(3S,4S)-4-[2-(3,5-Difluoro-2-pyridyl)pyrazol-3-yl]-3-methyl-1-piperidyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan- 1-one“A145” (2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[(3S,4S)-3-methyl-4-[2-(1-methylpyrazol-4-yl)pyrazol-3-yl]-1-piperidyl]propan-1- one“A146” (2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[4-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)pyrazol-3-yl]-1-piperidyl]propan-1-one “A147”(2R)-3,3,3-Trifluoro-2-hydroxy-2-methyl-1-[(3S,4S)-3-methyl-4-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)pyrazol-3-yl]-1-piperidyl]propan-1-one “A148” (2R)-3,3,3-Trifluoro-2-hydroxy-1-[(3S,4S)-4-[2-[4-(1-hydroxy-1-methyl-ethyl)phenyl]pyrazol-3-yl]-3-methyl-1-piperidyl]-2-methyl-propan-1-one “A149”(2R)-3,3,3-Trifluoro-1-[(3R,4S)-4-[3-(4-fluorophenyl)-1,2,4-triazol-4-yl]-3-methyl-1-piperidyl]-2-hydroxy-2-methyl-propan- 1-one“A150” (2R)-1-[(3R,4S)-4-[3-(2,4-Difluorophenyl)-1,2,4-triazol-4-yl]-3-methyl-1-piperidyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-propan- 1-one“A151” (2R)-3,3,3-trifluoro-2-hydroxy-1-[4-[3-[4-(1-hydroxy-1-methyl-ethyl)phenyl]imidazol-4-yl]-1-piperidyl]-2-methyl-propan-1-one “A152”(2R)-3,3,3-Trifluoro-1-[(3S,4S)-4-[3-(4-fluorophenyl)imidazol-4-yl]-3-methyl-1-piperidyl]-2-hydroxy-2-methyl-propan-1-one “A153”(2R)-3,3,3-Trifluoro-1-[4-[3-(4- fluorophenyl)-2-methyl-imidazol-4-yl]-1-piperidyl]-2-hydroxy-2-methyl-propan-1-one “A154”(2R)-3,3,3-Trifluoro-1-[4-[3-(4-fluorophenyl)-2-(hydroxyl-methyl)imidazol-4-yl]-1-piperidyl]-2-hydroxy-2- methyl-propan-1-one“A155” (2R)-3,3,3-Trifluoro-1-[4-[3-(4-fluorophenyl)-2-methoxy-imidazol-4-yl]-1-piperidyl]-2-hydroxy-2-methyl-propan-1-one

and pharmaceutically acceptable salts, tautomers and stereoisomersthereof. 8: A process for the preparation of the compound of the formulaI according to claim 1, the process comprising: reacting a compound offormula II

in which R, R¹ and R³ are as defined in formula I, with a compound offormula III

wherein L denotes Cl, Br, I or a free or reactively functionallymodified OH group, and/or converting a base or acid of the formula Iinto one of its salts. 9: A medicament, comprising at least one compoundof the formula I according to claim 1 and optionally a pharmaceuticallyacceptable carrier, excipient or vehicle. 10: A method for treating adisease, the method comprising: administering the compound of theformula I according to claim 1, including mixtures thereof in allratios, to a subject in need thereof, wherein the disease is cancer,diabetes, heart ischemia, insulin resistance syndrome, metabolicsyndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure,cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrialdisease, or mitochondrial encephalomyopathy. 11: The method according toclaim 10, wherein the disease is cancer of head, neck, eye, mouth,throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon,rectum, stomach, prostate, urinary bladder, uterine, cervix, breast,ovaries, testicles or other reproductive organs, skin, thyroid, blood,lymph nodes, kidney, liver, pancreas, brain, central nervous system, asolid tumor, or a blood-borne tumor. 12: A medicament, comprising atleast one compound of the formula I according to claim 1, includingmixtures thereof in all ratios, and at least one further medicamentactive ingredient. 13: A kit, consisting of separate packs of (a) aneffective amount of the compound of the formula I according to claim 1,including mixtures thereof in all ratios, and (b) an effective amount ofa further medicament active ingredient. 14: A pharmaceuticalcomposition, comprising the compound of claim 1, including mixturesthereof in all ratios.